My response to WinnieThePoo.

[SilentEchoes]

"You are sure it's [ALS/PD/AD] a toxic syndrome? Can you describe a mechanism of action for the disease process? You are sure it's not diet? Or stress? Of course you are sure. But unlikely to offer a viable solution to share. Meanwhile, those less blinkered [blinded by tunnel vision] research solutions on our behalf, for which I am grateful[.]"

I wrote this specifically for ALS on another forum - glutamate excitotoxicity is not exclusive to ALS.

A growing list of neurologic disorders are now understood to share a final common destructive metabolic pathway called excitotoxicity. Stroke, trauma, epilepsy, and neurodegenerative conditions, such as Parkinson's disease, Huntington disease, AIDS dementia complex, and ALS spectrum of disease, is not usually thought of as sharing the same mechanism of neuronal injury and death. pubmed.ncbi.nlm.nih.gov/328...

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.

Glutamate is an amino acid - one of a group of amino acid neurotransmitters in the brain, it is the principal excitatory neurotransmitter. Cerebral (brain) glutamate is derived solely from endogenous sources; mainly from α ketoglutarate, which is a product of the Krebs cycle [citric acid or TCA cycle]. The processing and transport of glutamate within the neuron are highly organized and coordinated interactions transported down the axon via a complex system of microtubules. Mitochondria also accompany these transport molecules, providing the required energy.

Upon reaching the axonal tip glutamate is released into the synaptic space between neurons. Glutamate is 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. The two main types of glutamate receptors are ionotropic and metabotropic. Ionotropic receptors are directly coupled to membrane ion channels and include AMPA and NMDA and kainate. These subtypes are named for their selective chemical agonists, which resemble glutamate but do not naturally exist in the brain. 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 NMDA 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. 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 receptors are affected by multiple factors, including magnesium (which blocks the channel), zinc (positive and negative modulator).

The chemical structures of glyphosate and those of its metabolite AMPA are similar to glycine and glutamate in a pH-dependent fashion, which are agonists of the N-methyl-d-aspartate receptor (NMDAR). Glutamate excitotoxic calcium overload in glutamate receptors play the key role in excitatory synaptic transmission in the central nervous system. Prolonged activation of extrasynaptic NMDARs causes calcium overload and apoptosis (death) of neurons. N-methyl-D-aspartate receptors (NMDAR) overactivation is linked to neurodegeneration.

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. The accumulation of high intracellular calcium levels triggers a cascade of membrane, cytoplasmic, and nuclear events leading to neurotoxicity.

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 over-activate a number of enzymes, and the generated feedback loops rapidly lead to neuronal self-digestion by protein breakdown, free radical formation, and lipid peroxidation.

Excessively stimulated NMDARs 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 Alzheimers and Parkinsons disease. 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 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.

Trauma is a mechanism that massively elevates the extracellular glutamate levels and can produce disastrous results with the exposure of the normal intracellular glutamate concentrations of about 2-5 μmol/L to the extracellular space. 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. Hypoxia deprives the neurons of oxygen and glucose, resulting in ATP energy failure. Neural toxicity occurs with the resultant activation of the cascade of glutamate receptor–dependent mechanisms. Mitochondria play a significant role in neuronal excitotoxicity and death.

In an attempt to interrupt, influence, or temporarily halt the glutamate excitotoxic cascade toward neuronal injury, drugs have been developed to block upstream release of glutamate. This category of drugs includes riluzole, lamotrigine, and lifarizine, which are sodium channel blockers. 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 intracellular events such 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). Glutamate excitotoxicity is the final common pathway resulting in neuronal injury for many seemingly unrelated disorders, including ischemia, trauma, seizures, hypoxia, and neurodegenerative disorders.

I was told by a prominent neurologist in 2017 that the research wasn't there yet for glyphosate neurotoxicity. It was, this information was published in 1999.

Read my post: Are you ready to kick neurotoxins to the curb?

I do not have tunnel vision - glyphosate and the other chemicals in Roundup act synergistically to cause neuronal injury. Organophosphates share a common denominator and that is some form of cyanide - which itself is a chemical compound that acts like a pseudo-halogen. Of course organochlorine hydrocarbons are a neurotoxin and their use has supposedly been greatly reduced.

SE