What Are Neurotoxins?
I'm glad you asked! Neurotoxins are organic compounds that are toxic to the central or peripheral nervous system. The dose often makes the poison. Some neurotoxins are actually beneficial in small amounts but become harmful in large quantities. Alcohol is one example, because small amounts may benefit cardiovascular health.
Read more about the definition of a neurotoxin here.
Neurotoxins may be classified as:
- Drugs of abuse (like methamphetamine)
- Endogenous neurotoxins (like quinolinic acid)
- Heavy metals (like lead)
- Solvents (like methanol)
- Additives or adulterants (like fluoride)
- Food-derived neurotoxins (like domoic acid or acrylamide)
- Research chemicals (like N-methyl D-aspartate)
- Proteins like botulinum toxin
- Some prescription drugs (e.g., Haloperidol)
From the neurotoxin list below, #7
6-OHDA (6-hydroxydopamine) is not a neurotoxin we’re directly exposed to; it is naturally produced in our brain when is chronically elevated from psychostimulants.
Domoic acid, is something you will be unlikely to be exposed to unless you consume shellfish that is prepared improperly. Heavy metals, especially lead and mercury, are among the most dangerous.
The lead-crime hypothesis is that the rise of violent crime in the 60's in the US was due to lead exposure.
Botulinum toxin (BTX) is a neurotoxic protein. For comparison, most of the other neurotoxins here are simple small molecules. Proteins are large in terms of molecular weight and size. Another neurotoxic protein is the misfolded prion protein.
BTX is produced by the bacterium Clostridium botulinum, which causes the disease botulism.
BTX has the distinction that it is the most acutely lethal toxin recognized to-date. It's estimated median lethal dose (LD50) is 1.3-2.1 ng/kg intravenously or 10-13 ng/kg when inhaled.
Surprisingly, botulinum is also used in medicine, cosmetics and research. You're probably familiar with Botox (marketed by Allergan) used to reduce fine lines and wrinkles.
Methamphetamine is markedly neurotoxic to the central nervous system (brain and spinal cord).
Methamphetamine is a dopamine-releasing agent that damages dopaminergic neurons via multiple mechanisms. Dopamine is the neurotransmitter implicated in reward, motivation, attention, hedonic tone, and Parkinson’s disease. Methamphetamine is significantly more neurotoxic than amphetamine.
Quinolinic is an endogenous neurotoxin – it’s produced in your brain naturally. Quinolinic is a downstream product of the amino acid l-tryptophan, metabolized by the kynurenine pathway. Quinolinic acid is an agonist at NMDA-type glutamate receptors. Excessive NMDA receptor activation causes excitotoxicity.
Fluoride is the anionic species of the element fluorine and is commonly used in toothpaste as an anti-cavity agent. The controversial fluoridation of the municipal water supply as a preventive measure against cavities is also an example of one of the largest acts of mass medication in history. Though the subject is highly controversial, developmental neurotoxicity attributed to fluoride is a well-documented possibility1, and it has been noted that fluoride has a detrimental effect on IQ 2.
Fluoride inhibits the activity of the glycolysis enzyme Enolase in a quasi-irreversible manner7, which undermines glucose metabolism and therefore ATP synthesis in the brain. The brain has enormous energetic/ATP requirements and glucose is virtually the only energy substrate for the brain (except for ketone bodies under exceptional conditions).
Acetaldehyde is used in industry as a precursor to acetic acid. Acetaldehyde is naturally occurring and can be found in coffee, bread, and some fruits. Acetaldehyde is a metabolite of ethanol because alcohol dehydrogenase oxidizes ethanol to acetaldehyde, and therefore ethanol comprises the largest dietary source of acetaldehyde. Acetaldehyde is carcinogenic and neurotoxic; it causes oxidative stress in the central nervous system (CNS) and contributes to the cognitive deficits associated with fetal alcohol syndrome 3.
Aluminum is ubiquitous in the environment and is used extensively in daily life, providing ample opportunity for exposure. Chronic exposure to aluminum is associated with a distinct pattern of neurobehavioral and neuropathological changes.
The prevailing hypothesis is that aluminum causes impairments in mitochondrial bioenergetics and induction of oxidative stress contributes to lipid peroxidation and disrupts the maintenance of membrane potentials by the sodium-potassium ATP-ase.
Epidemiological studies have revealed decrements in cognitive performance and a host of neurological symptoms in workers occupationally exposed to aluminum 4.
The larges dietary sources of acrylamide are coffee and starchy foods like potato chips and french fries. The formation of acrylamide is temperature-dependent; heating foods >120 degrees C promotes the formation of acrylamide.
Cigarette smoking causes three-fold greater acrylamide in plasma than any dietary factor. Acrylamide neurotoxicity arises from direct inhibition neurotransmission (via interference with the extracellular release machinery), inhibition of kinesin-based fast axonal transport and perturbations in neurotransmitter levels. Neurotoxicologists are most concerned about cumulative acrylamide burden from multiple sources over the course of decades.5
The neurotoxicity of mercury is widely recognized. Though we may no longer be exposed through thermometers since their re-invention, the aquatic bioaccumulation of methyl mercury in swordfish and sharks poses serious risks to human health.
Mercury damages the integrity of the blood brain barrier (which if compromised, allows other neurotoxins to enter the brain), and causes wholesale reductions in neuronal mRNA transcription. Mercury intoxication also disrupts glycolytic pathways (metabolism of glucose) and results in abnormal neuronal electrophysiology (e.g., abnormal depolarization/spiking) 6. Methyl mercury poses much greater risks than mercury alone, since organic mercury is absorbed and penetrates the CNS more readily.
The neurotoxicity of lead is so well-documented that no further discussion is required. Some have hypothesized that the environmental exposure to lead from pipes and paints causally corresponds to the rise of violent crime in the United States before the turn of the century.
Among other mechanisms of neurotoxicity, lead antagonizes N-Methyl-D-Aspartate Receptor (NMDAR)-dependent excitatory signaling, impairing long-term potentiation (LTP).
While it is very unlikely you will encounter environmental exposure to 6-hydroxydopamine (6-OHDA) per se, it is not uncommon for dopamine to be endogenously hydroxylated to 6-OHDA. 6-hydroxydopamine is a potent and selective neurotoxin that kills dopaminergic neurons, and is used in animal models to induce Parkinsonism, which occurs when 70% of the dopaminergic neurons in the substantial nigra have bene destroyed.
In vitro, 6-OHDA can be synthesized in the presence of iron or iron plus ascorbic acid. Any substance that increases extracellular dopamine concentrations (e.g., L-DOPA, dopamine re-uptake inhibitors, methamphetamine), will increase the formation of this toxic species, since more dopamine (DA) will be available for hydroxylation to 6-OHDA.
n-propylbromide was recently substituted for ozone-depleting solvents in industrial contexts. n-propylbromide is a common dry cleaner, spray adhesive, degreaser and aerosol solvent. Occupational exposure to n-propylbromide is linked to severe neural injury and the Occupational Safety and Health Administration (OSHA) has issued adamant warnings about n-propylbromide neurotoxicity.
The mechanistic features of n-propylbromide neurotoxicology are poorly characterized. Yet it is known that bromide itself is neurotoxic, causing a neurological syndrome in abusers of cough syrup due to the hydrobromide salt of dextromethorphan (i.e., DXM HBr). This phenomena is called brominism.
Organophosphates are the generic name for esters of phosphoric acid. Organophosphates are the basis of many insecticides, herbicides, and nerve agents.
Organophosphate pesticides are irreversible, suicide inhibitors of acetylcholinesterase, the enzyme that metabolizes acetylcholine in the central and peripheral nervous systems to clear the synapse and terminate cholinergic neurotransmission. Recent evidence suggests a link to adverse neurobehavioral development in children and fetuses.
Domoic acid is a kainic acid analogue and neurotoxin that causes amnesic shellfish poisoning. It is produced by algae and accumulates in shellfish, sardines and anchovies. Domoic acid is an extremely potent neurotoxin that concomitantly activates excitatory AMPA and kainic acid receptors resulting in profound excitotoxicity. Domoic acid rather selectively damages the hippocampus and amygdala, resulting in extreme impairments in short-term memory, confusion, seizures, and other neurological sequelae.
Choi AL, Sun G, Zhang Y, Grandjean P. Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect. 2012;120(10):1362-8. ↩
Borman B, Fyfe C. Fluoride and children’s IQ. N Z Med J. 2013;126(1375):111-2. ↩
Tong M, Longato L, Nguyen Q-G, Chen WC, Spaisman A, de la Monte SM. Acetaldehyde-Mediated Neurotoxicity: Relevance to Fetal Alcohol Spectrum Disorders. Oxidative Medicine and Cellular Longevity. 2011;2011:213286. doi:10.1155/2011/213286. ↩
Kumar V, Gill KD. Aluminium neurotoxicity: neurobehavioural and oxidative aspects. Arch Toxicol. 2009;83(11):965-78. ↩
Erkekoglu P, Baydar T. Acrylamide neurotoxicity. Nutr Neurosci. 2014;17(2):49-57. ↩
Chang LW. Neurotoxic effects of mercury–a review. Environ Res. 1977;14(3):329-73. ↩