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Advanced Neurology Role of immunosuppressants in autism

is adversely influenced by AZA. The author demonstrated 7. Differentiating rapamycin and
that AZA inhibits the expression of PPAR, the master azathioprine in the treatment of ASD
adipogenic regulator, in FAPs isolated from wild-type and
mdx mice, thereby decreasing their adipogenic potential. Rapamycin and AZA are two different drugs that have been
In addition, this is associated with reduced activity of the studied for their potential use in treating ASD, but they
AKT-mTOR axis. This study provides evidence that the work through different mechanisms and have different
AZA negatively regulates the adipogenic differentiation side effect profiles. Rapamycin is an mTOR inhibitor
of wild-type and mdx FAPs by preventing them from that can improve social behavior and synaptic function
reaching a terminally differentiated state. This negative in animal models of ASD. The drug has been studied in
modulation of PPAR by AZA is associated with the clinical trials in individuals with ASD, with some studies
reduced activation of AKT-mTOR signaling. Reggio et al. showing positive results in improving social behavior and
demonstrated that impaired PPAR expression correlates reducing repetitive behaviors [141] . However, the drug is
with blunted activation of the PI3K/AKT/mTOR axis, also associated with significant side effects, including an
indicating that azathioprine can inhibit the mTOR increased risk of infections, metabolic disturbances, and
pathway as well as mTORC1, which has been upregulated gastrointestinal symptoms. Azathioprine, on the other
in autism, and this elevation will be responsible for hand, is an immunosuppressant that has been studied
further elevation of NK cells, [110,132,133,138] . Azathioprine for its potential use in treating gastrointestinal symptoms
acts against IBD through the downregulation of commonly seen in individuals with ASD [142] . The drug
mTORC1 [139] . According to Green et al., AZA can inhibit works by suppressing the immune system, which is
the NK cell [140] . Based on the above information, we know thought to play a role in the pathogenesis of gastrointestinal
that AZA is an inhibitor of NK cells and can also inhibit symptoms in ASD. While some studies have suggested
the AKT/mTOR pathway through PPARγ. In addition, that AZA may be effective in improving gastrointestinal
it can limit FAP activity. This suggests that azathioprine symptoms in individuals with ASD, the drug is also
could be a potential treatment for autism, as it may help associated with significant side effects, including an
to reduce the activation of mTORc1, which can increase increased risk of infections and liver toxicity [143] . Further
NK cell levels as shown in Figure 6. research is needed to fully understand the potential

Figure 6. Role of azathioprine in treatment of autism via mTOR and natural killer cell. PI3K-AKT/mTOR signaling is upregulated in the progression of
autism. PI3K is activated by the receptor tyrosine kinase receptor. Activation of PI3K phosphorylates and converts phosphatidylinositol (4,5)-biphosphate
(PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3), leading to AKT activation. AKT signaling cascade inhibits the TSC1/2 complex by removing
its inhibition from mTORC1. Mutation in PTEN and TSC1/2 causes mTORC1 hyperactivation. Elevation of cytokines causes activation of receptor, which
leads to elevation of mTORC1. Also, PPAR ligands bind to PPAR receptor to further activate FAP gene, which leads to activation of mTORC1. This further
leads to activation of natural killer cell that causes activation of HLA, causing elevation of IFN due to which autism occurs. Azathioprine treats autism by
inhibiting PPAR from being activated, indirectly inhibiting mTORC1, and inhibiting natural killer cells.
Abbreviations: PPAR: Phosphoinositide-3-kinase; PIP2: Phosphatidylinositol (4,5) biphosphate; PIP3: Phosphatidylinositol (3,4,5) triphosphate; TSC1/2:
Tuberous sclerosis complex 1; mTOR: Mammalian target of rapamycin; PTEN: Phosphatase and TENsin homolog deleted on chromosome 10; PPAR:
Peroxisome proliferator-activated receptors; HLA: Human leukocyte antigen; IFN: Interferons; AKT: AK strain transforming.

Volume 2 Issue 2 (2023) 15 https://doi.org/10.36922/an.391