Exenatide, a GLP‐1 analog, has healing effects on LPS‐induced autism model: Inflammation, oxidative stress, gliosis, cerebral GABA, and serotonin interactions

Abstract

Previous studies have established anti‐inflammatory, antioxidant, and neuroprotective effects of Exenatide in the central nervous system. Since these mechanisms are thought to have important roles in the pathophysiology of autism, we hypothesized that Exenatide may have healing effects in autism. We tested this hypothesis by examining the effects of Exenatide in an experimental autism model created by lipopolysaccharide (LPS) exposure in the womb, with behavioral tests, histopathological examinations, and biochemical measurements. The autism model was created by administration of LPS (i.p) to pregnant rats on the 10th day of their pregnancy at a dose of 100 µg/kg. On postnatal 21st day, a total of four groups were formed from offspring with regard to sex distribution and treatment. After a 45‐day treatment, behavioral analysis tests were performed on rats. Subsequently, the rats were sacrificed and biochemical analysis [superoxide dismutase, tumor necrotizing factor alpha, nerve growth factor, 5‐hydroxyindoleacetic acid, and glutamic acid decarboxylase‐67] and histopathological analysis were performed. On the 10th day of the intrauterine period, LPS exposure was found to disrupt behavioral findings, increase inflammation and hippocampal gliosis, and decrease 5‐HIAA, GAD‐67, and NGF, especially in male rats. However, among the rats exposed to LPS in the intrauterine period, recipients of Exenatide demonstrated significant amelioration of findings. Exenatide therapy shows positive effects on behavioral disorders in an LPS‐induced autism model. This agent probably exerts its effects by suppressing inflammation and oxidative stress and reducing hippocampal gliosis. In addition, Exenatide has also been shown to positively affect cerebral serotonergic and GABAergic effects.

Maternal Immune Activation Induced by Prenatal Lipopolysaccharide Exposure Leads to Long-Lasting Autistic-like Social, Cognitive and Immune Alterations in Male Wistar Rats

“…Thus, it evokes a series of alterations at the inflammatory and behavioral level, mainly due to the negative effect exerted on formation of mature synapses [ 9 ]. This evidence has been reported in many studies, in which prenatal exposure to LPS produced immune [ 22 , 23 ] and behavioral dysfunctions such as communicative deficits, social impairments and stereotypies in rodents [ 24 , 25 , 26 , 27 ]. These findings are also corroborated by growing evidence demonstrating the role of neuropoietic cytokines in neurodevelopment, including glio- and neurogenesis [ 28 , 29 ], fate determination, cell death, neuronal–glia crosstalk and synaptic connectivity [ 2 , 30 , 31 , 32 ].…”

Granulocyte colony‐stimulating factor has a sex‐dependent positive effect in the maternal immune activation‐induced autism model

“…PSD‐95 facilitates synaptic maturation by recruiting/trafficking both N ‐methyl‐ d ‐aspartic acid receptors (NMDARs) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isox‐azoleproprionic acid receptors (AMPARs) and plays an important role in the maturation of the postsynaptic membrane (Ciafrè et al, 2020). Previous studies demonstrated that PSD‐95 deficiency was associated with psychiatric disorders such as schizophrenia (Lu et al, 2013) and ASD (Oliveira‐Junior et al, 2019; Solmaz et al, 2020). It was also reported that PSD‐95 knockout rats had significantly impaired social development compared with control subjects (Pitzer et al, 2008).…”

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

“…In an animal model of autism induced by LPS, it was shown that exenatide significantly reduced the hippocampal gliosis. Additionally, a positive effect was evident on brain serotonergic and GABAergic pathways exerted by exenatide [ 123 ]. In other studies, Malva sylvestris extract and fisetin (a phytomedicine-based potent antioxidant) showed a decrease in the astrogliosis and inflammatory or oxidative stress in damage induced by LPS in animal models of depression and memory impairment [ 124 , 125 ].…”