Magic™ Anti-GRM2 polyclonal antibody

Acetyl-L-carnitine (ALC) is a molecule derived from acetylation of carnitine in the mitochondria. Carnitine acetylation enables the function of CoA and facilitates elimination of oxidative products. Beyond this metabolic activity, ALC provides acetyl groups for acetylcholine synthesis, exerts a cholinergic effect and optimizes the balance of energy processes. Acetylcarnitine supplementation induces neuroprotective, neurotrophic and analgesic effects in the peripheral nervous system. In the recent studies, ALC, by acting as a donor of acetyl groups to NF-kb p65/RelA, enhanced the transcription of the GRM2 gene encoding the mGLU2 receptors, inducing long-term upregulation of the mGluR2, evidencing therefore that its long-term analgesic effects are dependent on epigenetic modifications. Several studies, including double-blind, placebo-controlled, parallel group studies and few open studies showed the effect of ALC in diseases characterized by neuropathies and neuropathic pain: the studies included diabetic neuropathy, HIV and antiretroviral therapy-induced neuropathies, neuropathies due to compression and chemotherapeutic agents. Double-blinded studies involved 1773 patients. Statistical evaluations evidenced reduction of pain, improvements of nerve function and trophism. In conclusion, ALC represents a consistent therapeutic option for peripheral neuropathies, and its complex effects, neurotrophic and analgesic, based on epigenetic mechanism, open new pathways in the study of peripheral nerve disease management.

Currently approved antidepressant drugs often take months to take full effect, and similar to 30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R, 6R)-hydroxynorketamine [(2R, 6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu(2)) and 3 (mGlu3) in the antidepressant-relevant actions of (2R, 6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R, 6R)-HNK prevented mGlu(2/3) receptor agonist (LY379268)-induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R, 6R)-HNK. The antidepressant-relevant behavioral effects and 30-to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R, 6R)-HNK administration were prevented by pretreatment with an mmGlu(2/3) receptor agonist and absent in mice lacking the Grm2, but not Grm3(-/-), gene. Combined subeffective doses of the mGlu(2/3) dreceptor antagonist LY341495 and (2R, 6R)HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R, 6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mmGlu(2) receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R, 6R)-HNK and inhibitors of mmGlu(2) receptor function in clinical trials for treatment-resistant depression either alone or in combination.