New insights into the mechanism of neurolathyrism: L-β-ODAP triggers [Ca2+]i accumulation and cell death in primary motor neurons through transient receptor potential channels and metabotropic glutamate receptors.

Abstract Neurolathyrism is a motor neuron (MN) disease caused by β- N -oxalyl-L-α,β-diaminopropionic acid (L-β-ODAP), an AMPA receptor agonist. L-β-ODAP caused a prolonged rise of intracellular Ca 2+ ([Ca 2+ ] i ) in rat spinal cord MNs, and the [Ca 2+ ] i accumulation was inversely proportional to the MN’s life span. The [Ca 2+ ] i rise induced by L-β-ODAP or ( S )-AMPA was antagonized completely by NBQX, an AMPA-receptor blocker. However, blocking the L-type Ca 2+ channel with nifedipine significantly lowered [Ca 2+ ] i induced by ( S )-AMPA, but not that by L-β-ODAP. Tetrodotoxin completely extinguished the [Ca 2+ ] i rise induced by ( S )-AMPA or kainic acid, whereas that induced by L-β-ODAP was only attenuated by 65.6 ± 6% indicating the prominent involvement of voltage-independent Ca 2+ entry. The tetrodotoxin-resistant [Ca 2+ ] i induced by L-β-ODAP was blocked by 2-APB, Gd 3+ , La 3+ , 1-(β-[3-(4-methoxy-phenyl)propoxy]-4-methoxyphenethyl)-1 H -imidazole hydrochloride (SKF-96365) and flufenamic acid, which all are blockers of the transient receptor potential (TRP) channels. Blockers of group I metabotropic glutamate receptors (mGluR I), 7-(hydroxyiminocyclopropan[b]chromen-1α-carboxylate ethyl ester (CPCCPEt) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) also lowered the [Ca 2+ ] i rise by L-β-ODAP. MN cell death induced by L-β-ODAP was prolonged significantly with SKF-96365 as well as NBQX. The results show the involvement of TRPs and mGluR I in L-β-ODAP-induced MN toxicity through prolonged [Ca 2+ ] i mobilization, a unique characteristic of this neurotoxin.