THC (Δ9-Tetrahydrocannabinol) Exerts Neuroprotective Effect in Glutamate-affected Murine Primary Mesencephalic Cultures Through Restoring Mitochondrial Membrane Potential and Anti-apoptosis Involving CB 1 Receptor-dependent Mechanism

• Published in: Phytotherapy research 2016-12, Vol.30 (12), p.2044-2052
• Main Authors: Nguyen, Chi Huu, Krewenka, Christopher, Radad, Khaled, Kranner, Barbara, Huber, Alexandra, Duvigneau, Johanna Catharina, Miller, Ingrid, Moldzio, Rudolf
• Format: Article
• Language: English
• Subjects: Animals; Cell Death; Female; Membrane Potential, Mitochondrial - drug effects; Mice; Neuroprotective Agents - pharmacology; Parkinson Disease; Pregnancy; Receptor, Cannabinoid, CB1 - administration & dosage; Receptor, Cannabinoid, CB1 - therapeutic use
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.5712

Aging-related neurodegenerative diseases, such as Parkinson's disease (PD) or related disorders, are an increasing societal and economic burden worldwide. Δ9-Tetrahydrocannabinol (THC) is discussed as a neuroprotective agent in several in vitro and in vivo models of brain injury. However, the mechanisms by which THC exhibits neuroprotective properties are not completely understood. In the present study, we investigated neuroprotective mechanisms of THC in glutamate-induced neurotoxicity in primary murine mesencephalic cultures, as a culture model for PD. Glutamate was administered for 48 h with or without concomitant THC treatment. Immunocytochemistry staining and resazurin assay were used to evaluate cell viability. Furthermore, superoxide levels, caspase-3 activity, and mitochondrial membrane potential were determined to explore the mode of action of this compound. THC protected dopaminergic neurons and other cell types of primary dissociated cultures from glutamate-induced neurotoxicity. Moreover, THC significantly counteracted the glutamate-induced mitochondrial membrane depolarization and apoptosis. SR141716A, a CB receptor antagonist, concentration-dependently blocked the protective effect of THC in primary mesencephalic cultures. In conclusion, THC exerts anti-apoptotic and restores mitochondrial membrane potential via a mechanism dependent on CB receptor. It strengthens the fact that THC has a benefit on degenerative cellular processes occurring, among others, in PD and other neurodegenerative diseases by slowing down the progression of neuronal cell death. Copyright © 2016 John Wiley & Sons, Ltd.