Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway

Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.