Motor neurone acetylcholinesterase release precedes neurotoxicity caused by systemic administration of excitatory amino acids and strychnine.
We have proposed that neuronal overactivation by either stimulation of excitatory receptors or hypofunction of inhibitory circuits is a cause of excessive acetylcholinesterase (AChE) release, which, in turn, can contribute to ALS/MND pathogenesis. We investigated histochemical and histopathological changes in cell populations of the mouse spinal ventral horn upon in vivo stimulation of glutamate receptors with L-aspartate (ASP, 10-50 mg/kg, intraperitoneal: i.p.), or blockade of glycine receptors with strychnine (STRY, 2 mg/kg, i.p.). ASP in P4-P13 (postnatal age in days) but not in older mice, and STRY irrespective of age, provoked rapid, striking depletions of motor neurone AChE, and appearance of AChE activity in astrocytes. This was followed by recovery of the enzyme in most motor neurones, astrocyte activation and statistically significant changes in: brain macrophage infiltration, loss of interneurones and motor neurones and neuronophagic images including rosettes of glial cells surrounding a central 'ghost-like' motor neurone. Although AChE release preceded the neuropathology found, it is not known if its uptake is a cause of glial activation. However, it has been shown that the enzyme potentiates non-N-metyl-D-aspartate receptors identical to those that mediate astrocyte activation. AChE activity produces protons and choline, possible microglial activators. These are putative routes towards long-lasting neuropathology.
Rodríguez-Ithurralde
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Division of Neuromyology, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay. drit@iibce.edu.uy
Maruri
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A
Rodríguez
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D000110:Acetylcholinesterase / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology*; D002452:Cell Count / Q000187:drug effects; D006651:Histocytochemistry; D007395:Interneurons / Q000187:drug effects; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013331:Strychnine / Q000494:pharmacology*; D013997:Time Factors
D018009:Receptors, Glycine; D001224:Aspartic Acid; D000110:Acetylcholinesterase; D013331:Strychnine