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].