Methamphetamine (MET) [BSA]

Methamphetamine (METH), also known as desoxyephedrine, is a highly addictive psychostimulant with very strong neurotoxicity to the central nervous system. METH abuse can cause a variety of disorders, including anxiety, psychosis, and paranoia. The mechanism of neurotoxicity is complex and is associated with dopaminergic neuronal dysfunction and loss. METH neurotoxicity can lead to damage to dopamine (DA) neuronal terminals in the brain of abusers and a sustained decline in striatal dopamine levels, triggering metabolic abnormalities and cognitive deficits. In METH-induced CNS inflammation, microglia and astrocytes are activated in several brain regions. Reactive glial cells secrete a variety of inflammatory factors that affect neuronal function. Various influencing factors both play an independent role and cross-promote each other, constituting a vicious circle of brain tissue damage.

During the process of METH causing neurotoxicity in dopaminergic neurons, it leads to excessive release of DA into the cytoplasm through the dopamine transporter. Rapid auto-oxidation of large amounts of DA and its formation of oxidative toxicants leads to oxidative stress, which mediates apoptosis and neuronal damage in dopaminergic neurons. On the other hand, it induces alterations in the mitochondrial respiratory chain within dopaminergic neurons and disrupts the outer mitochondrial membrane via the mitochondrial apoptotic pathway, affecting the balance of anti-apoptotic to pro-apoptotic protein ratios. METH also directly induces neuroinflammation, in which NFκB and inflammatory factors play an important role. It has been shown that METH-induced neuroinflammation in SH-SY5Y cells involves NFκB activation.

Figure 1. Possible mechanisms of methamphetamine-induced neurotoxicity
(Source: Jayanthi S, et al. 2021)

The end result of neurotoxicity is that cell death occurs. Numerous studies have shown that cytotoxicity due to METH exposure is closely related to programmed cell death in the form of apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Apoptosis induced by METH occurs and is regulated in relation to multiple signaling pathways, mainly the exogenous death receptor pathway, the endogenous mitochondrial pathway and the endoplasmic reticulum stress pathway. METH exposure not only harms the nervous system, but also causes serious damage to other systems. Some researchers have found a significant increase in apoptosis and a significant increase in lysis of Caspase-3 and PARP in METH-exposed rat cardiomyocytes. In METH-treated chronic lung injury, endoplasmic reticulum stress and endoplasmic reticulum stress-associated kinase pathways were activated to mediate apoptosis in alveolar epithelial cells.

METH
Desoxyephedrine