Highly Toxic Pigments

  • antimony white (antimony trioxide)
  • barium yellow (barium chromate)
  • burnt or raw umber (iron oxides, manganese silicates or dioxide)
  • cadmium red, orange or yellow (cadmium sulfide, cadmium selenide)
  • chrome green (Prussian blue, lead chromate)
  • chrome orange (lead carbonate)
  • chrome yellow (lead chromate)
  • cobalt violet (cobalt arsenate or cobalt phosphate)
  • cobalt yellow (potassium cobalt nitrate)
  • lead or flake white (lead carbonate)
  • lithol red (sodium, barium and calcium salts of azo pigments)
  • manganese violet (manganese ammonium pyrophosphate)
  • molybdate orange (lead chromate, lead molybdate, lead sulfate)
  • naples yellow (lead antimonate)
  • strontium yellow (strontium chromate)
  • vermilion (mercuric sulfide)
  • zinc sulfide
  • zinc yellow (zinc chromate)

Moderately Toxic Pigments

  • alizarin crimson
  • carbon black
  • cerulean blue (cobalt stannate)
  • cobalt blue (cobalt stannate)
  • cobalt green (calcined cobalt, zinc and aluminum oxides)
  • chromium oxide green (chromic oxide)
  • Phthalo blue and greens (copper phthalocyanine)
  • manganese blue (barium manganate, barium sulfate)
  • Prussian blue (ferric ferrocyanide)
  • toluidine red and yellow (insoluble azo pigment)
  • viridian (hydrated chromic oxide)
  • zinc white (zinc oxide)

“The Feast of the Rose Garlands-the painting that won the paint-off in 1506 between the Italian painters and Duerer. Duerer won”

by Dr. Elizabeth Garner and Joe Kiernan  /  January 2014


“Oil painting was an extremely dangerous occupation. All pigments were hand made using various extremely toxic materials, that if not handled with extreme caution AND CORRECTLY, could kill.

The process to develop the medium was usually made from a linseed oil base and or a variety of other similar oils as an additive.  Olive oil was a popular oil base mixture of the time, until it was discovered olive oil works it’s way through the paint and “drips out.”  This happens because the olive oil virtually never dried fully, and in time, with the added help of moisture in the patron’s home or church, it comes to the surface. It is known Leonardo da Vinci was adding wax to his paints to thicken them for better working because of this problem with olive oil.  Another trick Renaissance painters discovered was adding 5-10% honey to the mixture to preserve discoloration, especially in darker colors.

When producing pigments for colors a chemical changing process, known back then as alchemy, was needed in order to attain the copper sulfate necessary.  The more arsenious oxide used to do this, the deadlier the fumes produced and the more concentrated was the toxicity of the pigment powders. Apprentices were the ones usually assigned this mixing tasks.  The Masters knew this and had to teach them to be very very careful.

The colors of Green, Yellow, Red and Blue as being toxic in preparation and application and without a sealing coat to lock in fumes these would all continue to release poisonous fumes for its lifetime.  Even with a clear coat, in , as it cracks and chips, it releases toxic fumes again.  It’s really good that all of Dürer’s paintings are in museums now, where only the staff could be getting poisoned.


“Emperor Maximillian, the guy who didn’t pay Duerer for a year. Notice how Green the background is”

Greens pigments used in the Renaissance included Verdegreen, Malachite, Emerald Green, and Paris green. If green pigments are not sealed by a clear binding coat, this pigment will deliver a slow dose of concentrated arsenic gasses. The greens produced this way today are just as deadly. Mercury is a biproduct of creating green pigments. Green was deadly, the greener the color, the deadlier it was!


“Two of the apostles for the City Council Chambers”

Lighter colors used as in the whites and soft yellows were created using “white lead”.  White lead was a favorite choice of many for its consistancy and pliability to create an image over a few days.  It was highly toxic during production and application. We must also know that all these paintings including whites or flesh tones have had white lead added to the mixtures, palatte or surface of these works. If not sealed by a protective sealing top coat when applied, it will release poisonous lead gasses throughout its lifetime.


“The Haller Madonna. Notice it has red, blue, green and white”

For the pigments of blue, it was known that lapis lazuli was the prime choice, as was aquamarine.  These two pigments were very expensive and usually only ended up on the dress of royalty until the end of the 15th century.  Azurite was another excellent option for making a strong blue pigment in the 14-16th centuries.  It was acquired in deposits in silver veins and also through copper ore.  The mines that produced these minerals during the Renassaince time were in central Europe, mostly owned by the Nuremberg Patricians, and in France.

Azurite, on many paintings of the day, was often mislabled as lapis lazuli to cheat customers.  No matter how one worked with this product, the production and application of this color created many noxious fumes from arsenic sulphate. Another manufacturing process produced a highly toxic gas known as mercury cyanide.  Both byproducts were deadly.


“Realgar crystals”

Making red paint was a hugely sought out color by customers in their paintings during this time.  Realgar is the most likely choice of pigments in Germany.  This mineral was produced in Hungary, Bohemia, and Saxony, from mines once again owned by Nuremberg Patrician corporations and syndicates.  It can be found in the mines along veins of lead, silver and gold.

“Two of the four Apostle paintings”

Realgar was known at the time as “Ruby of arsenic” or “Ruby of Sulpher”.  It has wonderful qualities and is brilliant red, after a mining brutal production which spewed arsenic gasses into the air. Mining was very dangerous.  The powder was then collected and ground into the pigment powder.  If this powder were left in the sunlight, it would turn a shade of yellow.  This yellow is known as Orpiment another highly valued color in paintings.

“Orpiment pigment from realgar”

Mercury was a strong bi-product of producing the reds, especially Realgar and Vermillion when making copper sulphate.  The mercury is what was used to make the copper suphates.  For copper engraved metal plates because they have copper, using mercury to speed up the chemical reaction to polish the plate would be used, because they could.  These chemicals were always on hand. This mercury is a bi-product of producing the powder for the reds and the greens.

In the 15th-16th centuries, Spain was using Realgar to kill rats, some nations still use it for the same purpose today.  Even today Realgar and Orpiment are 2 of the 3 top elements used in the production of arsenic. Deadly stuff.


“Burkhard von Speyer”

Black at the time was made using the same toxic mediums, however the pigment itself was acquired mostly by scrapping the soot from lamps and or grinding up burnt bones and horns.  The process wasnt toxic, it was the oil base it was added to that was fatal.  It was to this mixture that Renaissance artists perfected the 5-10% honey addition to avoid color fading to a grey.


“The Borgias, the original crime family”

Arsenic is colorless and odorless. Arsenic poisoning was the choice of poisons of the period ala the Borgias.   Symptoms of arsenic poisoning begin with headaches, confusion, severe diarrhea, and drowsiness. As the poisoning develops, convulsions and changes in fingernail pigmentation called leukonychia striata  occurred. When the poisoning became acute, symptoms included diarrhea, vomiting, blood in the urine, cramping muscles, hair loss, stomach pain, and more convulsions. The organs of the body that are usually affected by arsenic poisoning are the lungs, skin, kidneys, and liver. The final result of arsenic poisoning is coma and death.  Arsenic is related to heart disease (hypertension related cardiovascular), cancer, stroke (cerebrovascular diseases), chronic lower respiratory diseases, and diabetes.

Mercury poisoning – Let’s remember also that in the Renaissance people with depression and syphilis were being treated with mercury, it was commonly available. They were all adding mercury to wine and it was known but not controlled that mercury made the wine taste a bit sweeter, so bad wine usually got more mercury added, although most of Nuremberg was consuming beer because the water was so polluted. A law was passed in late 16th century banning any land to add mercury to the wine.

Common symptoms of mercury poisoning include peripheral neuropathy (presenting as paresthesia or itching, burning or pain), skin discoloration (pink cheeks, fingertips and toes), swelling, and desquamation (shedding of skin), profuse sweating, tachycardia (persistently faster-than-normal heart beat), increased salivation, and hypertension (high blood pressure).

Affected children may show red cheeks, nose and lips, loss of hair, teeth, and nails, transient rashes, hypotonia (muscle weakness), and increased sensitivity to light. Other symptoms may include kidney dysfunction (e.g. Fanconi syndrome) or neuropsychiatric symptoms such as emotional lability, memory impairment, and / or insomnia.

Lead posioning – Symptoms may be different in adults and children; the main symptoms in adults are headache, abdominal pain, memory loss, kidney failure, male reproductive problems, and weakness, pain, or tingling in the extremities. Early symptoms of lead poisoning in adults are commonly nonspecific and include depression, loss of appetite, intermittent abdominal pain, nausea, diarrhea, constipation, and muscle pain. Other early signs in adults include malaise, fatigue, decreased libido, and problems with sleep. An unusual taste in the mouth and personality changes are also early signs.

All of these above said pigments are created, applied and continue to be deadly toxins until they are sealed within a clear coat of lacquer to seal in these toxins.  If they are left unsealed, or begin to flake or turn to a dust, it becomes a deadly painting of toxins. Deteriorating lead paint can produce dangerous lead levels in household dust and soil. Deteriorating lead paint and lead-containing household dust are the main causes of chronic lead poisoning.”


“In Part I of this series you were informed about how poisonous the pigments were that Albrecht or Margret Durer used in paintings, especially the reds, the greens, the blues, the whites, the yellows and the blacks. And we learned that German curators have already established that many of the paintings are overpainted, thus not sealing off the poison pigment(s) by either those who were jealous, understood the Cipher and wished to cover it up, or were bad restorers.

Even if a Dürer sealed a painting, all they would have to do is overpaint on the sealed coat to poison clients, just even a little bit.  Or if any paintings were covered with new pigments to conceal any trace of the Cipher by others who realized there were clues or were doing restoration, the new paint would be sitting on the surface in brilliant fashion, poisoning by the day.


You are now going to see who the Durers hated as obviously shown by the colors he selected, starting from the end of his life.  There are too many paintings that the Durers made sure were poisonous, but there are so many paintings, we will only be giving some of the top most obvious examples in this second part and continue in PART III.


Dürer did not paint these four paintings on commission. It was he who wanted to donate them to Nuremberg, his native city. On 6 October 1526 the artist offered The Four Holy Men to the city fathers of Nuremberg: `I have been intending, for a long time past, to show my respect for your excellencies by the presentation of some humble picture of mine as a remembrance; but I have been prevented from so doing by the imperfection and insignificance of my works… Now, however, that I have just painted a panel upon which I have bestowed more trouble than on any other painting, I considered none more worthy to keep it as a memorial than your excellencies.’ As it was common in many cities in Italy to bestow the town hall with a work of art that would serve as an example of buon governo, so did Dürer want to provide his native city with a work of his that had been purposefully made to this end.

The council gratefully accepted the gift, hanging the two works in the upper government chamber of the city hall. Dürer was awarded an honorarium of 100 florins. The four monumental figures remained in the municipality of Nuremberg until 1627, when, following threats of repression, they had to be sold to the elector of Bavaria, Maximilian I, a great enthusiast of Dürer’s work. On that occasion, however, the prince had the inscriptions, at the bottom of the paintings, sawed off and sent back to Nuremberg, as they were considered heretical and injurious to his position as the sovereign Catholic. The city handed them over to the museum in Munich in 1922, where they were rejoined with their respective panels.

“The Four Apostles”

Notice that these paintings are almost all lead white, vermillions, green, orpiment, and black.  Albrecht really wanted to take revenge on the whole government, the CITY COUNCIL, where every day they would be inhaling the noxious fumes. He even donated them! and got paid for his work!

“Way to Calvary made for the Holy Roman Emperor, Charles V, the son of Maximillian”

WAY to CALVARY, 1527

Made for EMPEROR CHARLES V, 1527, the boy king from whom Albrecht had to beg for his pension back. I don’t think you can find a blacker black painting with white lead poison than this.  It speaks for itself.  The Black pigments were DEADLY.


“Portrait of Hieronymous Holzschuher”

One of the top Nuremberg Patricians.  Lead White, Black, some orpiment


“Jacob Fugger, the Wealthy”

The presence of this portrait is documented, in the eighteenth century, in the gallery of the elector of Bavaria. Because of successive restorations, the top layer of colour is missing.

During the Diet of Augsburg, in 1518, Dürer portrayed Jakob Fugger in a charcoal drawing. The final painting, on canvas, differs from the drawing in the wealthier clothing of the subject, and, above all, in the framing: a half-bust in the drawing, a half-length in the painting.

Everybody hated the Fuggers in Nuremberg.  Blues, Lead white, black



Look at how green the background is, with reds, orpiment, white lead and black. Albrecht really hated his patron, two prints tell of his biggest humiliations and the Emperor didn’t even pay Albrecht for one year.


The man in the portrait holds a message on which the first few letters of his name can be read `P[or B]ernh’, the rest being hidden by the fingers of his left hand. This is almost certainly the painting to which Dürer refers in his Antwerp diary in late March 1521, recording that he had `made a portrait of Bernhart von Resten in oils’ for which he had been paid eight florins. Dürer’s reference is probably to Bernhard von Reesen (1491-1521), a Danzig merchant whose family had important business links with Antwerp. His name suggests that his family originated from Rees, a town on the Lower Rhine 100 miles east of Antwerp.


Look at how much red, black and lead white is in this painting

the 1521 ST. JEROME

Dürer painted St Jerome in Antwerp in March 1521 and presented the panel to his friend Rodrigo Fernandez d’Almada. He wrote in his diary: `I painted a Jerome carefully in oils and gave it to Rodrigo of Portugal.’ The panel was displayed in the merchant’s private chapel in Antwerp and was later taken back to Portugal. It is the only religious picture that Dürer painted in the Netherlands.

The figure of the saint is based on a drawing of an old bearded man. On the drawing, Dürer inscribed: `The man was 93 years old and yet healthy and strong in Antwerp.’

“The 1521 St Jerome painting”

This is an extremely encoded painting, with many nasty messages. Look at the green, the red, the orpiment


“The apostles James and Philippe”

Could we get any more white lead than in these paintings?  and Black and red? EVEN WHITE LEAD LETTERING


After he had achieved great fame, Dürer depicted the master who had taught him to paint. On it he inscribed: `This portrait was done by Albrecht Dürer of his teacher, Michael Wolgemut, in 1516′, to which he later added, `and he was 82 years old, and he lived until 1519, when he departed this life on St Andrew’s Day morning before sunrise.’ It is unclear from the inscription whether Wolgemut was 82 when he died or when the portrait had been painted three years earlier.

The fact that curators clearly say that Albrecht overpainted this painting with an additional inscription would have been enough to activate all the poisons.  Look at how green the deadly green background is, all the black, the inscription in orpiment.



There is an inscription near his head, monogrammed and dated 152(?). The last digit of the date is not clearly legible (1 or 4?), but the fact that the panel is oak indicates that the painting must have been carried out during Dürer’s trip to the Netherlands. The hypotheses regarding the name of the subject are various. The most frequent are: the one of Lorenz Sterck, an administrator and financial curator of the Brabant and of Antwerp, WHO WAS INVOLVED IN GETTING ALBRECHT’S PENSION BACK, and that of Jobst Plankfelt, Dürer’s innkeeper in Antwerp. These names are frequently suggested since Dürer writes in his diary that he had done oil portraits of them.

It is difficult to imagine an innkeeper who made himself depicted with a scroll in his hand. Whereas it seems much more plausible that the imposing subject characterized by a severe and scrutinizing gaze – clad in a silk shirt, a cloak with a fur collar, and a large beret – corresponds to a tax collector



This panel is mentioned in the inventory, dated 1598, of the Kunstkammer of Munich. The cloth around the hips was presumably expanded upward around 1600. The opinion that the Lucretia, all things considered, was “Dürer’s most unpopular work,” is undoubtedly widely shared.  THAT’S BECAUSE IT’S AN ENCODED PAINTING.


Lots of lead white, red, greenish-grey”



“We don’t know for whom these paintings were commissioned but we do know they were acquired by the Bishop of Breslau, Johan V Thurzo, a distant relation to the Fugger Family and then ended up in the collection of the Emperor Rudolf II in Prague. It’s clearly obvious by the  use of poisonous colors, it wasn’t someone the Dürers liked

“The 1507 Adam and Eva paintings”

Look at Eva’s flesh, it’s described as “whiter than white” than Adam’s skin-white lead everywhere, with the poisonous green right at the genitals, with the killer black paint in extraordinary amounts.


The Heller Altar was an oil on panel triptych by German Renaissance artists Dürer  and Mathhias Grünwald, executed between 1507 and 1509. In 1615, Dürer copyist Jakob Harrich painted a duplicate, which is now at the Staedel Museum of Franfurt. In 1615, the central panel, the only one by Dürer alone, was sold to Maximilian of Bavaria; a copy was ordered to replace the original in its location at the church’s high altar. The central panel was destroyed by a fire in Munich in 1729. The side panels, executed by Dürer’s assistants, were completed by four others commissioned to Matthias Grünewald in 1510. The side shutters were detached in the 18th century, and each of the two panels composing them were separated in 1804.

This altarpiece was commissioned by Jakob Heller (1460-1522), a wealthy merchant, member of the town council, and mayor of Frankfurt, either before or after Dürer’s second trip to Italy. Only the central element depicting the Assumption and Coronation of the Virgin was executed by Dürer himself. The altarpiece was destroyed by a fire in the residence of Duke Maximilian of Bavaria in Munich. Fortunately, a copy of the work, executed c. 1614 by Jobst Harrich of Nuremberg (c. 1580-1617) survived.  Albrecht was receiving many commissions after having won the “paint-off” with the Italians in Venice in 1506, especially from his old patron the Elector, Duke Friedrich of Saxony.  Albrecht wrote to Heller (of course the originals were lost but there were copies paid for by the Archduke Maximillian of Bavaria who acquired the paintings and wanted the provenance and documentation as well-those German scribe copyists were very busy).

He tells us that he was sick returning from Venice (all that partying) and he had to finish The Elector’s altarpiece first-The Martyrdom of the 10,000, and then he would start on Heller’s altarpiece. The outcome of the whole situation was that Heller misunderstood all of Albrecht’s intentions, almost sued him for breach of contract, trashed Albrecht’s reputation to everyone in town and pissed off Albrecht beyond comprehension.  In his last letter to Heller, Albrecht makes the following remarks: “I have painted it with great care, as you will see, using none but the best colors. It is painted with good ultramarine under and over about 5 or 6 times. And then after it was finished I OVERPAINTED IT TWICE MORE so that it may last a long time, for it is NOT MADE AS ONE USUALLY PAINTS. So don’t let it be touched or sprinkled with holy water…….And place the painting so that it hangs forward two or three finger-breadths, so it can be seen without glare.  And when I come to you in a year or two, or three, IF THE PICTURE IS PROPERLY DRY, it must be taken down and I will varnish it again with some excellent varnish THAT NO ONE ELSE CAN MAKE…”

“What the original painting of the Heller altarpiece is believed to have looked like”

Do we see enough blues and reds, and greens, and orpiment, and lead white to kill a horse, especially if the painting wouldn’t be dry for possibly three years?


The altarpiece depicts the legend of the ten thousand Christians who were martyred on Mount Ararat, in a massacre perpetrated by the Persian King Saporat on the command of the Roman Emperors Hadrian and Antonius. Dürer had depicted this massacre a decade earlier in a woodcut. The painting was commissioned by Frederick the Wise, who owned relics from the massacre, and it was placed in the relic chamber of his palace church in Wittenberg (ie. at home). Although Dürer had never before tackled a painting with so many figures, he succeeded in integrating them into a flowing composition using vibrant colour. Dürer’s gruesome scene depicts scores of Christians meeting a violent death in a rocky landscape, providing a veritable compendium of tortures and killings. The oriental potentate in the blue cloak and turban who is directing the action in the lower right corner of the picture, would in Dürer’s time have been perceived as a reference to the threat of Turkish invasion, because of the seizure of Constantinople in 1453. In the centre of the painting is the rather incongruous figure of the artist, holding a staff with the inscription: `This work was done in the year 1508 by Albrecht Dürer, German.’ The man walking with him through this scene of carnage is probably the scholar Konrad Celtis, a friend of Dürer’s who had died just before the painting was completed.

“The Marytrdom of the Ten Thousand made for the Elector, Duke Friedrich of Saxony, probably the 5th most powerful person in Germany. The duke later became protector of Martin Luther; without the Duke’s protection, Luther would never have survived”

I think you can see enough poisonous paints in this  painting to realize the Dürers also hated the Duke. 


“Unknown man”

Blacks, lead white, reds.  This striking portrait, painted in Venice, shows a thoughtful young man, richly dressed and dramatically set against a black background. His thick ginger hair, partly hidden by his dark hat, frames his face. The small part of his red shirt showing adds a dramatic touch of colour. Charles I acquired this work for the Royal Collection.


“Portrait of Burkhard von Speyer”

The sitter was identified as Burkard von Speyer after it was realized that he looks just like the man in a miniature in Weimar by an unknown artist, also dated 1506 and inscribed with his name. Nothing more is known about him, although presumably he originally came from Speyer, a town on the Rhine near Heidelberg. Burkard von Speyer also appears in The Altarpiece of the Rose Garlands. Wearing the same clothing, he is on the left side of the picture, just to the right of the first kneeling cardinal. You can’t get a blacker portrait with the reds, and the lead white than the one Albrecht made for Charles V


This is the painting that won the “paint-off” between the Venetian Italians and Dürer in 1506. This panel was painted for an altar for the German community in Venice, in the church of S. Bartolomeo near the Fondaco dei Tedeschi, the social and commercial centre of the German colony, where it remained until 1606. It was then acquired, after many negotiations, for 900 ducats by Emperor Rudolph II. According to Sandrart (1675), four men were hired to bring the packaged painting to the emperor’s residence in Prague. Stationed elsewhere during the invasion of the Swedish troops, the painting, already very damaged, returned to its place in 1635. It underwent a first restoration in 1662. In 1782, it was sold in an auction for one florin. After having passed through the hands of various collectors, it was acquired by the Czechoslovakian state in 1930. The painting, severely damaged chiefly in the centre portion, from the head of the Madonna and continuing downward to the bottom, was clumsily restored in the nineteenth century; in this restoration, the upper side portion, left of the canopy and to Saint Dominic’s head, was also included. Three copies of the work are known: one – considered the most important and which now belongs to a private collection – is attributed to Hans Rottenhamer, who sojourned in Venice from 1596 to 1606, where he took care of many acquisitions on behalf of Rudolph II; another is in Vienna; and the third, a rather modified version of the original, is in Lyon.

“Feast of the Rose Garlands”

Enough toxic paint to kill all the Italians and the Germans too.


The portrait is one of the first works of the artist during his second sojourn in Venice. It was painted in the autumn or in the winter of 1506.With reference to some of the details, it has been repeatedly made known that the portrait is unfinished.

“Portrait of an unknown Venetian Woman”

Reds, Lead white and black added for extra danger, left unfinished.


The Elector, Frederick the Wise of Saxony ordered this painting for the Schlosskirche (the church in the castle) in Wittenberg. It was once believed to be the central part of a polyptych, with, on the side wings, the story of Job, in Frankfurt and Cologne. However, this hypothesis has already been called into question. The Elector of Saxony then donated the painting to Emperor Rudolph II in 1603. An exchange with the Presentation at the Temple by Fra Bartolomeo brought it in 1793 from the gallery in Vienna to the Uffizi. Dürer framed and delimited a large space by an architecture composed of arches of a very refined perspective. The three kings arrived at this slightly elevated space from the back and after having climbed two steps. A single figure, sharply foreshortened, followed in their footsteps from the distant background. Only the upper half of his body is shown where he now stands at the bottom of the two steps. He is Oriental and wearing a turban. The heavy traveling bag he holds probably contains precious gifts for the infant Jesus. The Madonna is clad in azure clothes and cape, a white veil covering her head. She is holding out the infant, who is wrapped in her white veil, to the eldest king (who wears deadly GREEN clothing). He is offering the infant a gold casket with the image of Saint George, which the infant has already taken with his right hand. This is the only action that unfolds in the principal scene, except for the Oriental servant’s gesture of putting his hand in his bag. All the other characters are motionless; immersed in thought, they look straight ahead or sideways, creating the effect of a staged spectacle set with immobile characters.

Every color in this painting is horrendously toxic and right in the viewer’s face and nostrils.

“Adoration of the Magi made for The Elector, Duke Friedrich of Saxony”


“The Paumgartner Altar”

This triptych was commissioned by the brothers Stephan and Lukas Paumgartner for St Catherine’s Church in Nuremberg. The main panel depicts the Nativity, set in an architectural ruin. The left wing shows St George with a fearsome dragon and the right wing St Eustace, with both saints dressed as knights and holding identifying banners. A seventeenth-century manuscript records that the side panels were painted in 1498 and that the two saints were given the features of the Paumgartner brothers (with Stephan on the left and Lukas on the right). This is the earliest occasion on which an artist is known to have used the facial features of a donor in depicting a saint. But of course, Stephan was Albrecht’s lover.

The small figures at the bottom corners of the central panel are the Paumgartner family with their coats of arms. They were painted over in the seventeenth century, when donor portraits went out of favour, and were only uncovered during restoration in 1903. On the left behind Joseph are the male members of the family, Martin Paumgartner, followed by his two sons Lukas and Stephan and an elderly bearded figure who may be Hans Schönbach, second husband of Barbara Paumgartner. On the far right is Barbara Paumgartner (née Volckamer), with her daughters Maria and Barbara. Every color in this altarpiece is toxic and especially with the restoration could still be.


This panel is a large picture depicting Mary as the Mother of Sorrows. It was severely damaged in an attack when acid was thrown at it in 1988, and ten years have been spent restoring it. It is the central picture of the seven scenes from the Passion which are in the Gemäldegalerie in Dresden. The work was presumably ordered by Elector Frederick the Wise for the Wittenberg university chapel.

“The Virgin of the Seven Sorrows made for the Elector, Duke Friedrich of Saxony”

Black, lead white, Orpiment and blue (which doesn’t show in this picture well but I just saw the painting at the Staedel)-a deadly toxic painting for all to look at, worship, and inhale. And this brings us to the end of the examples of deadly toxic paintings the Dürers made for their “patrons.”  Thank goodness these are all in Museums where only the staff are still exposed to such dangers. We will discuss the family portraits, which are also made with deadly pigments in a future article.”


“The study’s results so far show that most Greenpoint backyard samples contain lead levels higher than the EPA’s recommended 400 ppm. Image: Franziska Landes


“…some 92 percent of Greenpoint backyards have at least one sample that exceeds the lead level that the EPA designates as safe for residential soil. Some yards contain seven or eight times more lead than they should — higher than the levels found in some polluted Peruvian mining communities Landes has studied…”

“This chart shows the number of children per 1,000 expected to have blood lead levels exceeding five micrograms per deciliter, the level at which the CDC recommends taking action. Source: NYC Dept of Health, 2015”


“Lead is a potent neurotoxin that accumulates in soft tissues and bone over time. Lead poisoning was documented in ancient Rome, Greece, and China. Lead(II) acetate (also known as sugar of lead) was used by the Roman Empire as a sweetener for wine, and some consider this to be the cause of the dementia that affected many of the Roman Emperors

Lead affects almost every organ and system in the body, targeting primarily the central nervous system but also the cardiovascular system, kidneys, and the immune system. Long-term exposure will cause significant impairment to the nervous system, severely damage the brain and kidneys and, in cases of exposure to high lead levels, ultimately cause death…”

Greenpoint, Brooklyn


“Lead accumulates and makes its home in our bones, where the body prefers to store it. This is done in an effort by the body to protect vital organs. From there, it is released into the blood stream… Meaning, lead can continue to be released into the blood long after exposure… Lead begins leaching into their bodies from the breakdown of bone tissue. Symptoms like fatigue and brain fog begin to occur due to lead toxicity…

It has also been found that exposure to lead early in life may cause neurodegeneration in later life. Among the many neurocognitive effects of lead are: brain damage, mental retardation, memory loss, vision loss, behavior problems, antisocial behavior, and even violence…”

“Vehicles using leaded gasoline that contaminated cities’ air decades ago have increased aggravated assault in urban areas”


-“Lead/pb causes mental regression in adults.  Lack of motor control, partial to full paralysis, coma, and death can be attributed to lead/pb.
-Lead/pb is proven to cause cancer.
-Lead/pb can make your kidneys stop working.
-Lead/pb causes confusion, dizziness, forgetfulness, emotional disorder like self doubt, lack of self confidence.
-Lead/pb can make you lose your balance when you are trying to walk.
-Lead/pb causes blurred vision.
-Lead can make you see things that are not there.
-Lead/pb can cause stuttering, slurred speech, dyslexia.  Lead/pb can make it difficult to talk out loud.
-Lead/pb makes your sense of smell go away.
-Lead/pb can make your teeth fall out earlier in life.
-Lead/pb can make you experience horrible anger.”


“NOTE: Potential hot spots of lead hazards in housing are identified based on indicators, not lead monitoring data. Because local data on lead contamination are generally unavailable, Scorecard relies on housing and demographic indicators to identify areas with housing that has a high risk of lead hazards. Scientific studies have demonstrated that housing built prior to 1950 and households with income below the poverty threshold have an elevated risk of lead contamination. Scorecard uses data from the 2000 U.S. Census for both of these risk factors to estimate potential lead hazards in housing.”

Lead neurotoxicity in children / Brain, Volume 126, Issue 1, 1 January 2003
by Theodore I. Lidsky & Jay S. Schneider

“The direct neurotoxic actions of lead include apoptosis, excitotoxicity, influences on neurotransmitter storage and release processes, mitochondria, second messengers, cerebrovascular endothelial cells, and both astroglia and oligodendroglia. Although all of lead’s toxic effects cannot be tied together by a single unifying mechanism, lead’s ability to substitute for calcium [and perhaps zinc (Bressler and Goldstein, 1991)] is a factor common to many of its toxic actions. For example, lead’s ability to pass through the blood–brain barrier (BBB) is due in large part to its ability to substitute for calcium ions (Ca2+). Experiments with metabolic inhibitors suggest that back‐transport of lead via the Ca‐ATPase pump plays an important role in this process (Bradbury and Deane, 1993). More direct evidence for the role of the Ca‐ATPase pump in the transport of lead into the brain has been provided by in vitro studies of brain capillary endothelial cells, the primary constituent of the BBB (Kerper and Hinkle, 1997a, b)…

Red Hook,Brooklyn

Apoptosis (programmed cell death) can be induced by a variety of stimuli. Apoptosis occurs when a cell activates an internally encoded suicide programme as a response to either intrinsic or extrinsic signals. One of the better characterized apoptotic cascade pathways has mitochondrial dysfunction as its initiator. Mitochondrial dysfunction initiated by the opening of the mitochondrial transition pore leads to mitochondrial depolarization, release of cytochrome C, activation of a variety of caspases and cleavage of downstream death effector proteins, and ultimately results in apoptotic cell death. While a variety of stimuli can trigger opening of the mitochondrial transition pore and cause apoptosis, a sustained intracellular increase in Ca2+ is one of the better‐known triggers; accumulation of lead is another. Lead disrupts calcium homeostasis, causing a marked accumulation of calcium in lead‐exposed cells (Bressler and Goldstein, 1991; Bressler et al., 1999). Lead, in nanomolar concentrations, also induces mitochondrial release of calcium (Silbergeld, 1992), thus initiating apoptosis…

Lead accumulates in and damages mitochondria (Anderson et al., 1996), the organelles mediating cellular energy metabolism. Haem biosynthesis, a function of normal mitochondrial activity, is affected by lead, with disruptive effects on synaptic transmission in the brain (see below, Indirect neurotoxic effects of lead). However, decreased mitochondrial functioning also can transform ordinarily benign synaptic transmission mediated by glutamate into neuron‐killing excitotoxicity (Beal et al., 1993)…”

How to stop lead poisoning / Feb 22nd 2018

“Lead has proved to be such a useful, malleable metal that it turns up everywhere, from water pipes to window flashing and printing type. It went into car batteries and petrol additives. It also helped make bright pigments, used to paint walls, metalwork and toys. Yet lead is also a poison, and its ubiquity makes it a pernicious one (see article). In the worst cases it causes comas, convulsions and death. More often it acts insidiously. It is a menace to toddlers, who are most likely to ingest contaminated dust and paint chips. Their brains are especially vulnerable. Only years after exposure are the results apparent in lower IQs, behavioural disorders and learning disabilities.

Far Rockaway, Queens

The dangers of lead have long been known. America banned it from paint 40 years ago, and by the late 1990s leaded petrol had been phased out in almost all rich countries. But the effects linger. Half a million American children are diagnosed with lead poisoning. The situation is more alarming in the poor world, where the use of lead-based paints is spreading. Curbing lead poisoning more than pays for itself. There is little excuse for poor countries to repeat the mistakes of rich ones.

The Romans did themselves no good by using lead for water pipes and sometimes even as a food sweetener. In 1786 Benjamin Franklin wrote a letter to a friend noting how the use of lead in distilleries had caused North Carolina to complain against New England Rum “that it poison’d their People, giving them the Dry Bellyach, with a Loss of the Use of their Limbs.”

“Members of the Michigan National Guard deliver water, filters, replacement cartridges and water test kits to Flint residents. Photo: Maj. Joe Cannon / U.S. National Guard via Flickr Creative Commons.”

In 2015 the Institute for Health Metrics and Evaluation, a research institute in Seattle, estimated that exposure to lead globally caused about 500,000 deaths that year and 12% of developmental disabilities, such as cerebral palsy and epilepsy. Another estimate is that lead poisoning costs Africa $135bn a year in lost output, the equivalent of 4% of GDP. The most urgent task is to stop putting more lead into the environment. As people in Asia and Africa become richer, they start to spruce up their homes. But the paint they use, even from pots labelled “lead-free”, often contains it. And they lack facilities to recycle lead batteries properly.

“National Guard members distribute water to citizens in Flint.”

It is neither difficult nor expensive to stop using lead. All countries should ban lead in paint. There should be no exemptions for industrial use, because the contamination spreads and industrial paint inevitably finds its way into the consumer market. Yet only four sub-Saharan African countries have formally enacted bans and local manufacturers are often unaware of the harm that lead causes.

The next step is to find and remove more of the lead introduced decades ago, particularly in rich countries. This will not be cheap, especially when the clean-up involves replacing lead pipes, as it often does in America. But the costs are worth it. The Pew Charitable Trusts, an NGO, reckons that every dollar spent on “lead abatement”—painting over old painted walls or removing flaking woodwork—saves at least $17 in medical and special-education costs, and lost productivity.

“Lee Anne Walters of Flint, Mich., pours gallons of bottled water into a bucket and pan to warm up for her twin sons to take a weekly bath. Her son, Gavin, 4, looking on, has been diagnosed with lead poisoning.”

In America investigations are typically carried out only in known cases of lead poisoning. However, children should not be used to test dangerous living conditions. It would be better to test older houses before problems appear. Cities and states need to make sure that landlords carry out remedial work. When poor owners cannot afford to fix their homes, the government should help as a prophylactic to save money on health care and education later. Charities that seek to help sick children and poor countries can contribute, too. There is no need to poison so many young minds.”




“Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) are overactivated by glutamatergic storm.”
“One of the key mechanisms of glutamate-induced neuronal cell injury is in the release of glutamate by microglial cells (13, 14). Microglial cells are essentially the resident immune cells of the brain and nervous system. Once the free pool of glutamate increases, glutamate receptors, such as NMDA are over-stimulated. This then causes a massive influx of calcium ions into cells, resulting in neuronal cell damage, and cell death.”
“Reading these studies, the reader will find discussion of damaged or overly sensitive glutamate receptors, and malfunctioning glutamate transport. The reader will also find discussion of “glutamate pools” where excess glutamate is stored – and then sometimes released to cause brain damage. Rarely mentioned, however, is the role that ingestion of excess amounts of processed free glutamate (MSG) might play in producing these diseases; and if mentioned at all, it is by researchers outside of the United States.”

“Neuroradiologists may encounter, on a daily basis, a challenging diversity of neurologic disorders, including stroke, trauma, epilepsy, and even neurodegenerative conditions, such as Huntington disease, AIDS dementia complex, and amyotrophic lateral sclerosis (1), but this spectrum of disease is not usually thought of as sharing the same mechanism of neuronal injury and death. These and a growing list of other neurologic disorders are now understood to share a final common destructive metabolic pathway called excitotoxicity (2, 3), which has been the focus of intense investigative efforts in the neurosciences over the past several decades (3–31).

Excitotoxicity refers to an excessive activation of neuronal amino acid receptors. The specific type of excitotoxicity triggered by the amino acid glutamate is the key mechanism implicated in the mediation of neuronal death in many disorders. The discovery of excitotoxic injury is a major clue in the search for answers to such fundamental questions as why neurons die in disease states and what is the precise or critical mechanism of neuronal death.

This overview introduces and reviews some of the major concepts of glutamate excitotoxicity. Familiarity with this intriguing pathologic process will enhance the understanding of the neuroimaging changes of many neuropathologic processes, facilitate a conceptual model for some of the newer treatment strategies for some disorders (ie, stroke and trauma), and perhaps cultivate new directions for neuroimaging. The organization of this article follows the excitotoxic process from the formation of glutamate to neuronal death.

Glutamate excitotoxicity is a broad and rapidly evolving field of study with many important nuances that have necessarily been oversimplified or, unfortunately, omitted from this review for the sake of reasonable brevity. The reader is referred to the exponentially expanding literature and some of the sources listed in the reference section for additional information.

Glutamate is an amino acid and one of a group of amino acid neurotransmitters in the brain, although it is the principal excitatory neurotransmitter. More basically, amino acids (Fig 1) consist of a central carbon atom (α carbon) bonded to a carboxyl group (COOH) and an amino group (NH3). A distinctive side chain (R group), which characterizes each amino acid, links to the α carbon. Glutamate (Fig 2) consists of the side chain CH2CH2COO (COOH ending [γ carboxyl group] for glutamic acid) attached to the α carbon, while the closely related glutamine (Fig 3A and B) is created from glutamate with ammonia added at the γ carboxyl group by glutamine synthetase, forming the CH2CH2CONH2 side chain R group. Cerebral glutamate is derived solely from endogenous sources; mainly from α ketoglutarate, which is a product of the Krebs cycle (citric acid cycle, TCA [tricarboxylic acid] cycle).

fig 1.
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fig 1. Amino acid. Typical amino acid consists of a central alpha carbon () that is bonded to a carboxyl group (COOH) on one side and an amino group (H3N) on the other side. Each amino acid is characterized by a distinctive molecular group (R) or side chain attached to the α carbon.

fig 2. Glutamate. The side chain, or R group, of glutamic acid is CH2CH2COOH. The carboxyl group of the side chain is designated the γ carboxyl group, which becomes fully ionized at neutral pH and is therefore frequently written with a negative charge (COO). The term glutamate (instead of glutamic acid) is used to indicate this negative charge or ionized state at physiological pH.

fig 3.
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fig 3. A, Glutamine. This closely related amino acid is formed from glutamate with the addition of an amino group at the γ carboxyl of the side chain. B, This formation of an amide linkage at the γ carboxyl group requires the enzyme glutamine synthetase and the process is adenosine triphosphate (ATP)-dependent. This reaction is also a major mechanism for the detoxification of cerebral ammonia.

The neuronal glutamate considered here acts as a neurotransmitter, which is the method of communication between neurons. This interaction between neurons may be either excitatory or inhibitory. The major excitatory amino acid neurotransmitters are glutamate and aspartate, while GABA (γ-aminobutyric acid), glycine (aminoacetic acid), and taurine are inhibitory.

The processing and transport of glutamate (Fig 4) within the neuron are highly organized and coordinated interactions among multiple cytoplasmic organelles resembling the frenetically detailed but choreographed mosaic activities of an ant farm (32). Glutamate, like other neurosecretory substances, is initially synthesized by the endoplasmic reticulum and then transported to the Golgi apparatus for additional processing. Emerging from the opposite surface of the Golgi apparatus and wrapped inside a vesicular (bilipid) membrane, glutamate is then transported down the axon via a complex system of microtubules. Antegrade motion down the axon on the microtubules is mediated by molecules called motor kinesin, whereas cytoplasmic dynein generates retrograde motion. Mitochondria also accompany these transport molecules, providing the required energy. Upon reaching the axonal tip (Fig 5), the vesicle with the enclosed glutamate merges with the presynaptic membrane by the process called exocytosis to release the glutamate into the synaptic space between neurons. The vesicular membrane is then recycled and transported back up the neuronal axon in a retrograde fashion via the microtubular network. The synaptic glutamate is finally freed to interact with specific receptor sites on the postsynaptic membrane of the adjacent neuron to initiate an important cascade of molecular events within that neuron (Fig 6).

fig 4.
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fig 4. Neuronal glutamate processing and transport. Glutamate is processed by the endoplasmic reticulum and Golgi apparatus in preparation for fast axonal transport, which also requires other transport proteins and mitochondria. When glutamate emerges from the “trans” face of the Golgi apparatus, it is encapsulated inside a neurosecretory vesicle, which consists of a bilipid membrane. These vesicles are transported down the axon along microtubule tracks to be deposited at the tip of the axon near the presynaptic membrane. Waves of axonal membrane depolarization would trigger the release of the glutamate into the synaptic space by exocytosis, which is exhibited by the merging of the neurosecretory vesicles with the postsynaptic membrane to free the packaged glutamate. The empty vesicle would then be recycled back to the neuronal body by retrograde transport along the microtubular tracks (adapted from [32])

fig 5.
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fig 5. A–C,Electron micrographs show neurosecretory vesicles releasing neurotransmitter molecules by exocytosis on the presynaptic membrane. Numerous small neurotransmitter substances can be seen in the synaptic space (open arrows). These neurotransmitters will then settle on and activate receptors on the postsynaptic membrane. Dark circles by straight solid arrows represent vesicles filled with neurotransmitters. Light partial circles by curved solid arrows represent the vesicle merging with the presynaptic membrane and releasing neurotransmitter into the synaptic space (adapted from [32])

fig 6.
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fig 6. Pictorial display of the neurotransmitter glutamate (orange) released into the synaptic space and docking with the glutamate receptor site on the postsynaptic membrane. The activation of the glutamate receptor then opens the ion channel coupled to the receptor, allowing the passage of extracellular calcium (yellow) into the intracellular cytosol, which in turn triggers a series of biochemical events (adapted from Schornak S, BNI Q 11:1995)
fig 7. Ionotropic and metabotropic receptors. The ionotropic receptors NMDA (purple) and AMPA (red) are directly coupled to ion channels. The metabotropic receptors (blue and orange) activate intermediary molecules such as G protein affecting multiple cytoplasmic enzymes to produce molecules, such as IP3, that increase cytosol calcium concentrations. Also depicted are modulatory substances, such as spermine, which facilitate calcium influx, and receptor complex inhibitors, such as zinc, magnesium, and PCP. L-2-amino-4-phosphonopriopionic acid (L-AP4) and aminocyclopentyl dicarboxylic acid (ACPD) receptors are classified as metabotropic, as they are coupled to intermediary G proteins (G) that activate phosphodiesterase (PDE) for L-AP4 receptors and form inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP3) for the ACPD receptors via phospholipase C. 2-amino-3-phosphonopriopionic acid (AP3) and quinoxaline-2,3-dione (NBQX) are antagonists for ACPD and AMPA receptors, respectively.

Postsynaptic Anatomy

The interaction of glutamate with the postsynaptic membrane requires a review of glutamate receptors (Fig 7). The two main types of glutamate receptors are ionotropic and metabotropic. Ionotropic receptors are directly coupled to membrane ion channels. The metabotropic receptors are coupled to intermediary compounds, such as G protein, and modulate intracellular second messengers, such as inositol-1,4,5-trisphosphate (IP3), calcium, and cyclic nucleotides. The directly coupled ionotropic receptor, which is the primary consideration of this review, can be further subdivided into three subtypes: NMDA (N-methyl-D-aspartate), AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate), and kainate. These subtypes are named for their selective chemical agonists, which resemble glutamate but do not naturally exist in the brain. This nomenclature may seem awkward, but it offers the convenience and consistency of grouping the various cerebral and cerebellar receptors according to their responses to the chemical tools that are used to evaluate or stimulate them.

Excessive accumulation of intracellular calcium is the key observed process leading to neuronal death or injury, and the NMDA receptors activate channels that allow the influx of extracellular calcium (and sodium). Overstimulation of this type of glutamate receptor would then lead to neuronal calcium overload. Some types of AMPA and kainate receptors can contribute to intracellular calcium overload because their coupled membrane ion channels are at least partially permeable to calcium.

The influx of calcium and sodium from glutamate receptor stimulation results in membrane depolarization, which can also activate voltage-dependent calcium channels. These other calcium channels then allow further calcium influx, aggravating the intracellular calcium overload initiated by overstimulation of the glutamate receptors and opening of the associated ion channels. The four main types of voltage-dependent calcium channels considered here are named for their specific properties: T (transient current), N (found in neurons), L (long duration current, large conductance channels), and P (found in Purkinje cells of the cerebellum). The L channel is not the most prevalent type but it disproportionately contributes to calcium-mediated neuronal injury because of the prolonged calcium influx that occurs with activation of this voltage-dependent conduit.

Multiple modulatory sites, however, complicate some of the ionotropic receptors. It may be helpful to think of the receptors as a receptor-channel complex with the receptor closely linked to and controlling the adjacent ion channel. Modulatory sites are separate areas on the receptor and the channel in which other molecules can influence the function of the receptor site or channel. On the NMDA receptors, glycine (once considered a laboratory contaminant) acts as a required coagonist. Hydrogen ions (a reflection of pH) suppress receptor activation. Polyamines, such as spermine, however, can relieve proton block and potentiate NMDA receptor activation in a pH-dependent fashion. The NMDA receptor channels are affected by multiple factors, including magnesium (which blocks the channel), zinc (positive and negative modulator), and multiple drugs, such as dizocilpine and phencyclidine ([PCP, “angel dust”] channel blocker) (Fig 8).

fig 8.
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fig 8. Schematic representation of NMDA, AMPA, and kainate receptors as receptor–channel complexes. Glutamate docks with the receptor, which opens the coupled channel to allow the intracellular influx of extracellular calcium. Other molecules (such as magnesium, zinc, and PCP) can influence receptor function by interacting with several receptor and channel modulatory sites


Glutamate excitotoxic calcium overload can be appreciated from the perspective of the normal mechanisms of neuronal calcium homeostasis. Intracellular cytosolic free calcium is maintained at very low concentrations (micromolar) relative to free extracellular calcium. Plasma membrane calcium transporters regulate this cytosolic free calcium concentration. Membrane transporters in general have been classified as antiporters, symporters, and ATP-coupled active transporters (Fig 9). These transporters are membrane protein compounds that are coupled to energy sources and change the distribution of substrate ions or molecules across a membrane. Antiporters and symporters are called secondary transporters because they use the energy from an existing ion gradient to drive the passage of another ion or molecule in the same (symporter) or opposite (antiporter) direction across a membrane as the energizing ion. Movement through the neuronal membrane is achieved by a change in the conformation of the protein-substrate complex. Complexing with two or more substrates is required to initiate conformational transitions in antiporters (opposite direction coupling) and symporters (same direction coupling). The primary transporters (ATP-coupled active transporter) couple a chemical reaction to the protein conformational transitions that supply the metabolic energy required to generate concentration gradients of substrate ions across the membrane. Calcium is controlled by the antiporter and plasma-membrane calcium pump (PMCA). The antiporter, which has a low affinity but high transport capacity for calcium, moves calcium out of the neuron by a sodium–calcium exchange mechanism. The sodium gradient across the membrane drives this exchanger. The PMCA, on the other hand, has a high affinity but low transport capacity for calcium. This active pump transports one Ca2+ for each ATP hydrolyzed. One distinguishing feature of the PMCA is the enhanced activation of the pump by binding Ca2+/calmodulin, which results in a 20- to 30-fold increase in the affinity of the substrate Ca2+ site (33).

fig 9.
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fig 9. Membrane channels and transporters. The ion channels are pathways to allow the diffusion of ions across the cell membrane. These channels can be opened or closed by changes in membrane voltage, associated ligands, and so on. Excessive intracellular calcium is detrimental to neuronal health, and a calcium gradient is maintained across the neuronal membrane mostly by three main types of transporters. The antiporters use an existing ion gradient (usually established by active or ATP-dependent transport) to transport calcium ions (green) in the opposite direction of the energizing ion (ie, sodium). Symporters transport calcium in the same direction of the energizing ion (blue). Both antiporter and symporters are considered secondary transporters because they derive energy from an existing gradient. The ATP-coupled active transporter is considered a primary transporter that uses ATP to affect the transmembrane movement of calcium to establish its gradient (adapted from [32])

The mitochondrion and endoplasmic reticulum are also significant sources of calcium stores. An antiporter mechanism maintains high calcium concentrations in the mitochondria by moving free calcium from the cytosol to the mitochondria while an antiporter and an ATP-dependent active pump sequester the endoplasmic reticulum calcium (Fig 10).

fig 10.
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fig 10. Calcium homeostasis. Membrane transporter (antiporter and ATP-dependent transporter) maintain a much higher extracellular calcium (small circles) concentration than the cytosol. The endoplasmic reticulum and mitochondria are important sources of intracellular extracytosolic calcium. These internal sources of calcium can be released into the cytosol when provoked by specific agents, such as the second messenger (IP3) actions on the endoplasmic reticulum (adapted from [32])

Glutamate receptor overstimulation increases intracellular calcium by directly opening ion channels and secondarily affecting calcium homeostatic mechanisms. As mentioned, the initial glutamate receptor opening of the sodium/calcium channels not only allows the influx of calcium but also causes membrane depolarization. The depolarization would in turn activate the voltage-dependent calcium channels, which would further increase the intracellular calcium levels. The decreased sodium gradient across the cell membrane caused by the glutamate receptor–coupled channels, however, would also reduce the ability of the sodium gradient–dependent antiporter to remove intracellular calcium. Superimposed disorders that decrease ATP production (ie, hypoxia, neurodegenerative disorders, etc) would adversely affect the activity of the ATP-dependent calcium transporters as well as the energy-dependent sodium potassium pump, which would then also affect the transmembrane sodium gradient and therefore the antiporter function.

Intracellular Toxic Events

The accumulation of high intracellular calcium levels triggers a cascade of membrane, cytoplasmic, and nuclear events leading to neurotoxicity. Elevation of the intracellular calcium, however, appears to be a complex issue, because inducing similar intracellular calcium levels by using a metabolic inhibitor such as cyanide or membrane depolarization with potassium causes less permanent neuronal damage than with glutamate. The glutamate-induced elevated calcium levels proceed to overactivate a number of enzymes, including protein kinase C, calcium/cadmodulin-dependent protein kinase II, phospholipases, proteases, phosphatases, nitric oxide synthase, endonucleases, and ornithine decarboxylase (Fig 11). Some of these enzymes can also produce positive feedback loops to accelerate the downward spiral toward neuronal death (Fig 12). Activation of phospholipase A, for example, would generate platelet-activating factor and arachidonic acid and its metabolites. Platelet-activating factor directly contributes to the excitotoxic cascade by increasing glutamate release. Arachidonic acid inhibits reuptake of glutamate from the synaptic space, leading to further activation of glutamate receptors and more arachidonic acid formation. Increased arachidonic acid levels form oxygen free radicals, which activate phospholipase A, leading to more arachidonic acid formation. These enzymes and the generated feedback loops rapidly lead to neuronal self-digestion by protein breakdown, free radical formation, and lipid peroxidation.

fig 11.
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fig 11. Excessive accumulation of intracellular calcium caused by overactivation of the glutamate receptor sites stimulates multiple enzymes, which are involved in normal neuronal development and function, resulting in damage to the cell membrane, cytoskeleton, and DNA.

fig 12. Abnormally increased activation of some enzymes, such as phospholipase A, can cause an intracellular feedback cycle of events, leading to cell death.

Another important activated enzyme is nitric oxide synthase, which forms nitric oxide. Nitric oxide performs a variety of normal biological functions but the excessively stimulated NMDA receptors will produce abnormally increased levels of nitric oxide and superoxide ions. These substances may react and form peroxynitrite, which is extremely toxic, resulting in neuronal death. Nitric oxide can damage DNA as well as inhibit mitochondrial respiration, which in turn would create more free radicals and cause additional membrane depolarization. The nitric oxide–initiated neurotoxic cascades are important components of the mechanism of cell death in many neurodegenerative disorders, including Huntington disease (34–54).

Excessive Glutamate Accumulation

The key process that triggers the entire excitotoxic cascade is the excessive accumulation of glutamate in the synaptic space. This can be achieved by altering the normal cycling of intracranial glutamate (Fig 13) to increase the release of glutamate into the extracellular space or to decrease glutamate uptake/transport from the synaptic space, or by frank spillage of glutamate from injured neurons.

fig 13.
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fig 13. Neuronal glutamate that is released into the synaptic space is normally removed from the synaptic space by adjacent glial cells, in which the glutamate is converted to the closely related glutamine, which can then readily diffuse back into the neuron. Glutamine is converted back to glutamate in the neuron.

fig 14. Diagram shows sequence of events occurring in cerebral ischemia leading to neuronal death. (Free radical formation and lipase activation are also related to the increased intracellular calcium, although the two processes are not directly connected to the increased calcium by arrows in this schematic.)

Trauma is a blunt mechanism that massively elevates the extracellular glutamate levels. Normal extracellular glutamate concentration is about 0.6 μmol/L. Substantial neuronal excitotoxic injury occurs with glutamate concentrations of 2 to 5 μmol/L. Traumatic injury to neurons can produce disastrous results with the exposure of the normal intracellular glutamate concentrations of about 10 μmol/L to the extracellular space. Mechanical injury to a single neuron, therefore, puts all of the neighboring neurons at risk. Significant collateral injury occurs to surrounding neurons from this type of glutamate release. One recent therapeutic strategy is to immediately treat persons with injuries to the head or spinal column with glutamate receptor blockers to minimize the spread of neuronal death beyond the immediate physically disrupted neurons.

Several mechanisms of excess glutamate accumulation probably come into play in ischemia (Fig 14). Abnormal release of glutamate from its storage sites in neuronal vesicles is at least one factor. A feedback loop is generated as this released glutamate stimulates additional glutamate release. Ischemia also causes energy failure that impairs the reuptake by glutamate transporters. These transporters behave as symporters, which rely on the sodium gradient across cell membranes to move glutamate against its concentration gradients into the cell. The sodium gradient, however, is maintained by an energy-dependent pump that fails in ischemia. Such failure not only affects glutamate transport out of the synaptic space but also causes the transporters to run backward, becoming a source of extracellular glutamate rather than a sink for it. Ischemia deprives the neurons of oxygen and glucose, resulting in energy failure; however, energy failure itself is not particularly toxic to neurons. Neural toxicity occurs with the resultant activation of the cascade of glutamate receptor–dependent mechanisms. If these receptors are blocked by appropriate antagonists, the neurons can survive a period of deprivation of oxygen and metabolic substrate. This is the rationale for the recent development and trial of glutamate receptor blockers to treat acute ischemic events (55–66). While an infarcted zone cannot be salvaged, the hope is to prevent surrounding damage to the at-risk adjacent penumbra.

These receptor blockers may also be critical in the developing arena of interventional and pharmacologically related attempts to reestablish perfusion to acutely ischemic areas of the brain. Tissue reperfusion and increased oxygen concentrations to ischemic areas without concurrent halting of the excitotoxic cascade either at the receptor or intracellular levels may increase rather than decrease neuronal damage by providing additional free radicals in the form of superoxide anions as well as by increasing the intracellular cytosol calcium levels by stimulating the release of mitochondrial calcium stores.

Acceptance of the significant role of mitochondria in neuronal death and excitotoxicity is reflected in the rapidly expanding literature on this topic during the past decade (26, 49, 67–81). Preliminary investigations into the mechanisms of mitochondrial calcium homeostasis have already inspired several therapeutic neuroprotective strategies.

A number of drugs have been developed and used in an attempt to interrupt, influence, or temporarily halt the glutamate excitotoxic cascade toward neuronal injury (82–88). One strategy is the “upstream” attempt to decrease glutamate release. This category of drugs includes riluzole, lamotrigine, and lifarizine, which are sodium channel blockers. The commonly used nimodipine is a voltage-dependent channel (L-type) blocker. Attempts have also been made to affect the various sites of the coupled glutamate receptor itself. Some of these drugs include felbamate, ifenprodil, magnesium, memantine, and nitroglycerin. These “downstream” drugs attempt to influence such intracellular events as free radical formation, nitric oxide formation, proteolysis, endonuclease activity, and ICE-like protease formation (an important component in the process leading to programmed cell death, or apoptosis). Apoptosis occurs as part of the complex process of neuronal death, but many investigators believe that excitotoxicity and apoptosis are essentially different mechanisms that have intersecting influences (27, 56, 89–106).

Neuroradiologic Observations

Routine neuroimaging studies reflect the sequela of glutamate excitotoxic damage. The spreading involvement of adjacent brain tissue beyond the immediate area of insult in trauma and infarction is one example, and the delayed presentation of these conditions is another. The insidious brain parenchymal loss noted on imaging studies in patients with AIDS dementia is also thought to be related to glutamate excitotoxic injury.

The development of spectroscopy at 0.5 T has provided an intriguing opportunity to observe the combined glutamate and glutamine (glx) peak in vivo (107). Delineation of this peak is enabled by the coalescence of the multiplets of glx at this field strength (Figs 15 and 16). The collapse of the γ and β multiplet resonances can be briefly summarized by the ratio of δ/J (δ = chemical shift, J = spin-spin coupling constant), which governs the spectral appearance of a strongly coupled multiplet structure such as glx. The spin-spin coupling constant is determined by molecular structure and is independent of field strength, whereas the chemical shift between coupled spins is a linear function of field strength. Therefore, as the ratio of δ/J approaches zero (or decreases), the multiplet collapses toward a single resonance line.

fig 15.
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fig 15. MR spectrum of a normal frontal lobe obtained at 1.5 T with a single-voxel point-resolved spectroscopy (PRESS) technique at 1500/41 (TR/TE).
fig 16. MR spectrum of the same frontal lobe as in figure 15 obtained at 0.5 T with a single-voxel PRESS technique at 1500/41. Note the more conspicuous glx peak.

Interesting clinical observations are then possible and have been made with the ability to examine the glx peak. Glutamate excitotoxicity has been the implicated mechanism of neuronal injury in mesial temporal sclerosis with consistent, strong supportive experimental data (108–121). Elevated glx peaks have been observed in the hippocampi of these patients (Fig 17A and B) (122). Mitochondrial disorders, such as MELAS (mitochondrial myopathy, encephalopathy, lactacidosis, and stroke), are functionally ischemic, although there is no hypoperfusion but rather an inability to utilize the available oxygen. Imaging findings may be variable, but spectroscopic sampling of apparently normal-appearing areas of the brain by routine imaging can reveal not only the expected lactate peaks but also an elevated glx peak (Fig 18A and B). Even neurodegenerative disorders, such as Huntington disease, have been evaluated by this technique, and elevated glx peaks have been observed in the basal ganglia (123–125).

fig 17.
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fig 17. A, Coronal T2-weighted MR image of a patient with right mesial temporal sclerosis. B, MR spectrum obtained from a voxel (indicated in A) centered in the region of the patient’s right hippocampal formation shows an elevated glx peak.

fig 18.
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fig 18. Proton-density–weighted MR image in a patient with MELAS shows bilateral abnormal signal intensity changes at the periphery of the occipital lobes. B, MR spectrum obtained at 0.5 T shows elevated glx and lactate peaks from a sampling of the normal-appearing right frontal lobe of same patient (voxel placement indicated in A).


Glutamate excitotoxicity is the final common pathway resulting in neuronal injury for many seemingly unrelated disorders, including ischemia, trauma, seizures, hypoglycemia, hypoxia, and even some neural degenerative disorders. Familiarity with this process is important for neuroradiologists because of its central position in many of the disorders encountered in daily practice. This area has been one of the most intensely investigated fields in the neurosciences over the past several decades, and the information generated from this work will clearly influence our basic understanding of many neurologic disorders.”


  • 1 Presented in part at the annual meeting of the American Society of Neuroradiology, San Diego, May 1999.


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  • Received March 26, 2001, American Society of Neuroradiology