Synergistic disruption of the blood-brain barrier in tree shrews by Methamphetamine and HIV-1 Tat via TRPM2-Mediated astrocyte inflammation.

Methamphetamine (METH) abuse and HIV infection have emerged as two major public health concerns worldwide. Both METH and the HIV-1 Tat protein (Tat) can enter central nervous system through blood-brain barrier (BBB) and exert neurotoxic effects. However, the specific mechanism underlying their synergistic disruption of BBB remains unclear. Herein, co-culture models of endothelial cells and astrocytes and tree shrews were used to explore the role and mechanism of the Transient receptor potential M2 (TRPM2) in mediating the synergistic BBB damage induced by METH and Tat. In the tree shrew experiment, METH and/or Tat exhibited neurotoxicity, and the combination of them yielded more severe toxic effects characterized by tight junction protein loss, albumin leakage, astrocyte activation, neuroinflammation, and astrocytic TRPM2 activation. Similarly, in vitro experiments revealed that METH and Tat decreased tight junction proteins and transendothelial electrical resistance while increasing the flux of sodium fluorescein, and triggering astrocyte-mediated inflammation and astrocytic TRPM2 activation. However, pharmacological inhibition of TRPM2 mitigated the above-mentioned BBB damage and astrocyte-related inflammation both in vitro and in vivo. Furthermore, inhibition of TRPM2 mitigated METH + Tat-induced stereotypical behavior and anxiety-like behavior in tree shrews. Critically, astrocyte-specific TRPM2 knockdown in tree shrews effectively prevented METH and Tat-induced neuroinflammation and BBB damage, and ameliorated the associated behavioral impairments. This study revealed that METH and Tat could synergistically activate astrocytic TRPM2 channels to induce astrocyte-derived inflammatory response, and ultimately resulted in BBB injury. These findings highlight astrocyte-mediated inflammation as an important mechanism by which METH and Tat synergistically damage the BBB, and the TRPM2 channel represents a promising therapeutic target, providing novel insights into the mechanism of neurotoxicity caused by METH and HIV-1 Tat.