Tetrahydropalmatine Regulates BDNF through TrkB/CAM Interaction to Alleviate the Neurotoxicity Induced by Methamphetamine

Tetrahydropalmatine (THP) has analgesic, hypnotic, sedative, and other pharmacological effects. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, growth, and development. However, their mechanism of action in methamphetamine (MA)-induced neurotoxicity remains unclear. This study aims to explore the important role of BDNF in MA neurotoxicity and whether THP can regulate BDNF through the interaction between tyrosine kinase receptor B (TrkB)/calmodulin (CAM) to alleviate the neurotoxicity induced by MA. SD rats were randomly divided into control, MA, and MA + THP groups. Stereotyped behavior test, captive rejection test, open field test (OFT), and Morris water maze (MWM) were used to evaluate the anxiety, aggression, cognition, learning, and memory. Extracted hippocampus and mesencephalon tissue were detected by Western blot, HE staining, and immunohistochemistry. TUNEL staining was used to detect apoptosis. MOE was used for bioinformatics prediction, and coimmunoprecipitation was used to confirm protein interactions. Long-term abuse of MA resulted in lower weight gain ratio and nerve cell damage and caused various neurotoxicity-related behavioral abnormalities: anxiety, aggression, cognitive motor disorders, and learning and memory disorders. MA-induced neurotoxicity is related to the down-regulation of BDNF and apoptosis. THP attenuated the MA-induced neurotoxicity by decreasing CAM, increasing TrkB, phosphorylating Akt, up-regulating NF-κB and BDNF, and inhibiting cell apoptosis. MA can induce neurotoxicity in rats. BDNF may play a vital role in MA-induced neurotoxicity. THP regulates BDNF through TrkB/CAM interaction to alleviate the neurotoxicity induced by MA. THP may be a potential therapeutic drug for the neurotoxic and neurodegenerative diseases related to MA.