Chronic
neuroinflammation-induced anomalous glutamate receptor
activation has been identified as one of the important factors in
the pathogenesis of autism spectrum disorder (ASD). Thus, the current
study was designed to elucidate the neuroprotective effect of the
granulocyte colony-stimulating factor (G-CSF), a haemopoietic growth
factor, an anti-inflammatory, and a neuroprotectant to decipher the
underlying mechanism(s) in the valproic acid (VPA)-induced experimental
model of ASD. Experimentally, the ASD rat model was induced by a single
dose of VPA (600 mg/kg; i.p.) on gestation day 12.5 to the pregnant
female rats. After birth, pups were treated with vehicle, normal saline
0.9% i.p., risperidone (2.5 mg/kg; i.p.), and G-CSF (10, 35, and 70
μg/kg; i.p.) from postnatal day (PND) 23 to 43. All the groups
were subjected to various developmental and behavior tests from birth.
The rats were sacrificed on PND 55, and their brain was excised and
processed for biochemical parameters (oxidative stress, inflammatory
markers, BDNF), histological examination (H&E, Nissl staining),
NMDA, and AMPA receptor expression by immunohistochemistry, western
blot, and real-time polymerase chain reaction evaluation. Also, the
possible interaction of the G-CSF with NMDA and AMPA receptors was
evaluated using the in-silico method. The results
of the study showed that in VPA-exposed rats, postnatal treatment
of G-CSF rescued all the behavioral abnormalities, oxidative stress,
and inflammatory parameters in a dose-dependent manner while risperidone
did not show any significant results. The in-silico analysis showed the direct interaction of G-CSF with NMDA and AMPA
receptors. The upregulated expression of NMDA and AMPA both in the
prefrontal cortex as well as hippocampus was alleviated by G-CSF thereby
validating its anti-inflammatory and excitoprotective properties.
Thus, G-CSF demonstrated neuroprotection against the core symptoms
of autism in the VPA-induced rodent model, making it a potential candidate
for the treatment of ASD.