4.2 Methamphetamine
Methamphetamine (METH), a widely abused illicit drug and the most commonly abused drug, has long been known to cause neurotoxicity[23]. Neuroinflammatory processes are associated with brain dysfunction caused by the abuse of the drug. METH is a highly addictive stimulant, and exposure to METH can cause irreversible neuronal damage and further lead to neuropsychiatric symptoms and cognitive impairment[51]. It has been shown that METH administration leads to apoptosis of striatal dopaminergic neurons and astrocyte-associated neuroinflammation, thereby amplifying METH-induced activity of neuronal reward changes[22, 52]. However, how METH induces neuroinflammatory responses within the central nervous system (CNS) remains unclear.
Much of the literature has confirmed that IL-1α, IL-1β, IL-6, IL-8, and IL-15 in the interleukin family are all related to METH-induced neuroinflammation[53]. Furthermore, METH exposure increased LPS-induced IL-6 production in the NAc region[54]. However, clinical trials on the population have confirmed that after the use of meth, IL-2R, IL-6, IL-8 and IL-10 in the blood will change and are correlated with the severity of psychotic symptoms and cognitive dysfunction[55].
Mechanisms related to the occurrence of neuroinflammation caused by METH through the interleukin family have also been studied. One of the mainstream claims is that cytokines released by activated glial cells have a dual effect on brain injury. METH-induced miR-146a triggers the IL-1β autoregulatory loop to regulate innate immune signaling T cells in CD4. Elevated levels of interleukin 1α were noted 4 hours after Tat + MA treatment[56]. Metformin also protects the brain from METH-induced neurodegeneration by reducing interleukin-1β (IL-1β) expression in the hippocampus through mediating CREB/BDNF or Akt/GSK3 signaling[57]. Systemic administration of METH increases the expression of the pro-inflammatory cytokine interleukin 6 (IL-6) mRNAs in the ventral tegmental area (VTA), demonstrating that METH-induced neuroinflammation is at least partially mediated by TLR4-IL6-6 signaling in VTA, which has the downstream effect of increasing dopamine in the NAc shell[58]. At the same time, some pieces of literature pointed out that the selective Jun NH2 terminal Kinase 1/2 (JNK1/2) inhibitor (SP600125) potentiates METH-induced striatal cell loss after administration, causing the increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and interfering with drug-induced IL-15 expression[59]. Some other articles also explored the mechanism at the cellular level. For example, METH treatment enhances the aggregation of apoptosis-associated speck-like proteins of the inflammasome adapter containing the caspase recruitment domain (ASC), induces activation of the IL-1β convertase caspase-1, and generates lysosomes and Mitochondrial damage, triggering the activation of the microglial inflammasome and eventually leading to neuroinflammation[60]. METH-induced microglial cell death in a concentration-dependent manner and also resulted in marked morphological changes and reduced cell proliferation. The anti-apoptotic effect of TNF-α is mediated by activating the IL-6 signaling pathway, especially the janus kinase (JAK)-STAT3 pathway, which induces the downregulation of Bax/Bcl-2, leading to its apoptosis[61]. It has also been suggested that exposure of astrocytes to MA leads to the activation of NF-κB via phosphorylation of IκB-α, increasing MA induction of IL-6 and IL-8 via the NF-κB pathway[62] and leading to neuroinflammation. Similar to opioids, there is also evidence that METH produces neuroinflammation by activating the innate immune Toll-like receptor 4 (TLR4). The canonical TLR4 antagonists LPS-RS and TAK-242 attenuate METH-induced microglial NF-κB activation. However, METH exposure up-regulates the expression of CXCR1, which can increase the expression of interleukin-8 through the NF-κB pathway, and further activate CXCR1 to induce METH-related neuronal apoptosis[63, 64]. These results provide a new understanding of the neurobiological mechanisms underlying acute METH reward, including critical roles in central immune signaling, and provide new targets for drug development to treat drug abuse.
It has also been reported in the literature that the neuroinflammation of METH can be treated by interfering with the interleukin family. METH can activate microglial cells to produce neuroinflammatory molecules. There is literature mentioning that METH reduces cell viability and activates IL-1β and IL-6 in the striatum and hippocampus in a concentration and time-dependent manner[21, 65, 66]. METH causes oxidative stress and inflammation, leading to the overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Attenuation of METH toxicity and inhibition of expression of cytotoxic factor genes associated with ROS and RNS neutralization in striatal microglia reduced neuroinflammation[67, 68]. Additional literature has suggested a protective effect of melatonin against the neurotoxic signature of METH, characterized by striatal reactive gliosis. Therefore, melatonin may be one of the neuroprotective agents induced by METH toxicity or other immunogens[69]. Interestingly, the protective role of molecular hydrogen against oxidative stress and related neurodegenerative diseases has recently been elucidated. Hydrogen therapy can ameliorate METH-induced neurotoxicity and spatial learning and memory impairment. Hydrogen molecules significantly inhibited the damage of hippocampal neurons after high-dose METH exposure. It can inhibit the elevation of IL-6 in the hippocampus, thereby ameliorating METH-induced neurotoxicity[70]. Besides, SN79 attenuates the increase of METH-induced mRNA of members of the IL-6 proinflammatory cytokine family, thereby preventing neuroinflammation[71]. Recently a dimeric fusion protein, thioredoxin-1, has also been frequently suggested as a new therapy for the cognitive alterations that occur in individuals with METH abuse. It blocks IL-1 signaling in the hippocampus, thereby attenuating the loss of METH-associated cognitive decline[21, 72]. METH not only acts on IL-1 and IL-6, but also increases the level of interleukin-2 (IL-2) and decreases the level of IL-10 in the striatum. However, the overexpression of Trx-1 reversed the above-mentioned effects induced by METH, further indicating that overexpression of Trx-1 suppressed METH-induced inflammation[73]. Some literature also indicates that lactulose is also a neuroinflammation inhibitor. Lactulose is a poorly absorbed derivative of lactose. It effectively reduced the neurotoxicity of METH in rats, and weakened the METH-induced up-regulation of oxidative stress by inhibiting the over-expressions of IL-1β and IL-6 in the striatum[64, 74, 75]. Another intriguing study concerns death from hyperthermia in case of METH overdose, with the main mechanism being the increased expression of IL-1β in the hypothalamus. In contrast, σ receptor antagonists can attenuate METH-induced hyperthermia by modulating hypothalamic IL-1β mRNA[65]. A final review of the literature reveals that the non-psychoactive cannabinoid, cannabidiol (CBD), has potent anti-inflammatory and immunosuppressive properties. CBD prevented METH recovery by reducing the gene expression of IL-1β, IL-6, and IL-10 in the prefrontal cortex (PFC) and hippocampus[76].