Methamphetamine (METH) is an addictive stimulant drug that has many negative consequences, including toxic effects to the brain. Recently, the induction of inflammatory processes has been identified as a potential contributing factor to induce neuronal cell degeneration. It has been demonstrated that the expression of inflammatory agents, such as cyclooxygenase 2 (COX-2), depends on the activation of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT). Moreover, the excessive elevation in cytosolic Ca²⁺ levels activates the cell death process, including calpain activation in neurons, which was diminished by the overexpression of the calpain inhibitor protein, calpastatin. However, it is unclear whether calpain mediates CaN-NFAT activation in the neurotoxic process. In the present study, we observed that the toxic high dose of METH-treated neuroblastoma SH-SY5Y cells significantly decreased cell viability but increased apoptotic cell death, the active cleaved form of calcineurin, the nuclear translocation of NFAT, and COX-2 levels. Nevertheless, these toxic effects were diminished in METH-treated calpastatin-overexpressing SH-SY5Y cells. These findings might emphasize the role of calpastatin against METH-induced toxicity by a mechanism related to calpain-dependent CaN-NFAT activation-induced COX-2 expression.

甲基苯丙胺（METH）是一种令人上瘾的刺激性药物，具有许多负面影响，包括对大脑的毒性作用。最近，炎症过程的诱导已被确定为诱导神经元细胞变性的潜在促成因素。已经证明，诸如环氧合酶2（COX-2）之类的炎症剂的表达取决于钙调神经磷酸酶（CaN）的活化和活化T细胞的核因子（NFAT）。此外，胞质Ca ²⁺过度升高水平会激活细胞死亡过程，包括神经元中的钙蛋白酶激活，而钙蛋白酶抑制剂蛋白钙蛋白酶抑制素的过表达降低了钙蛋白酶的激活。但是，尚不清楚钙蛋白酶是否在神经毒性过程中介导CaN-NFAT活化。在本研究中，我们观察到有毒的高剂量METH处理的神经母细胞瘤SH-SY5Y细胞显着降低了细胞活力，但增加了凋亡性细胞死亡，钙调神经磷酸酶的活性裂解形式，NFAT的核转运和COX-2的水平。然而，这些毒性作用在过甲基苯丙胺处理的钙蛋白酶抑制剂过表达的SH-SY5Y细胞中已减弱。这些发现可能通过与钙蛋白酶依赖性CaN-NFAT激活诱导的COX-2表达有关的机制，强调了钙蛋白酶抑制素对METH诱导的毒性的作用。