The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells

Recent studies suggested contribution of homocysteine (HCY) to neurodegenerative disorders and migraine. However, HCY effect in the nociceptive system is essentially unknown. To explore the mechanism of HCY action, we studied short‐ and long‐term effects of this amino acid on rat peripheral and central neurons. HCY induced intracellular Ca 2+ transients in cultured trigeminal neurons and satellite glial cells (SGC), which were blocked by the NMDA antagonist AP‐5 in neurons, but not in SGCs. In contrast, 3‐((2‐Methyl‐4‐thiazolyl)ethynyl)pyridine (MTEP), the metabotropic mGluR5 (metabotropic glutamate receptor 5 subtype) antagonist, preferentially inhibited Ca 2+ transients in SGCs. Prolonged application of HCY induced apoptotic cell death of both kinds of trigeminal cells. The apoptosis was blocked by AP‐5 or by the mGluR5 antagonist MTEP. Likewise, in cortical neurons, HCY‐induced cell death was inhibited by AP‐5 or MTEP. Imaging with 2′,7′‐dichlorodihydrofluorescein diacetate or mitochondrial dye Rhodamine‐123 as well as thiobarbituric acid reactive substances assay did not reveal involvement of oxidative stress in the action of HCY. Thus, elevation of intracellular Ca 2+ by HCY in neurons is mediated by NMDA and mGluR5 receptors while SGC are activated through the mG luR5 subtype. Long‐term neurotoxic effects in peripheral and central neurons involved both receptor types. Our data suggest glutamatergic mechanisms of HCY‐induced sensitization and apoptosis of trigeminal nociceptors. image We show that NMDA and mGluR5 receptors in trigeminal and cortical neurons and mGluR5 receptors in glial cells mediate homocysteine (HCY)‐induced [Ca 2+ ] i elevation whereas HCY‐evoked apoptosis involves both NMDA and mGluR5 receptors. This study revealed migraine‐related short‐ and long‐term effects of this redox active aminoacid within the nociceptive system and highlights potential targets for anti‐nociception and neuroprotection.