Effect of sex differences and time of oxytocin administration on treatment of rat model of autism spectrum disorder: Focused on necroptosis markers

Abstract

Autism is a neurodevelopmental disorder. A variety of molecular and cellular abnormalities leads to behavioral deficits in autism. Nevertheless, its etiology and treatment strategy are not completely understood. Oxytocin has recently shown improvements in social functioning. This study aimed to evaluate the necroptosis pathway for the neuroprotective effects of oxytocin in the valproic acid‐induced autism spectrum disorder model. The autism spectrum disorder was induced by valproic acid on gestational day 12.5 (600 mg/kg, intraperitoneally). Offspring received intranasal oxytocin (1 μg/μL) on the 21st and 40th days after birth. The offspring behaviors were scrutinized by self‐grooming, marble‐burying, three‐chamber, and Morris water maze tests. Western blot was performed on the hippocampus and amygdala tissues to investigate the expression of RIP3 and MLKL markers. The valproic acid group demonstrated more anxiety, repetitive behaviors, and expression of RIP3 and MLKL markers, and less social interaction and spatial memory compared with the control group. Oxytocin considerably improved social interactions, preference for social novelty, and memory. The elevated expression of RIP3 and MLKL markers in valproic acid‐induced autistic rats were alleviated after treatment with oxytocin. We also highlighted the importance of age and gender in autism spectrum disorder interventions. Our findings suggested that oxytocin administration was as an effective treatment in two areas of repetitive/stereotyped behaviors, social interactions/cognitive function. Notably, early administration of oxytocin resulted in better therapeutic responses in autism‐like behaviors. The molecular tests introduce oxytocin as a potential candidate for reducing the expression of necroptosis mediators in the brain. This reinforced our hypothesis that the necroptosis pathway takes part in autism spectrum disorder.

Acute brain injury and nanomedicine: sex as a biological variable

“…The microbiome also exhibits significant and well-studied sex differences, which have been proposed to impact the gut-brain axis leading to sex differences in disease phenotype and drug ADME (Jašarević et al, 2016;Hokanson et al, 2023). For intranasal dosing, drugs first encounter the nasal passageways and mucosal barriers, for which mucous pH, secretion, and clearance have been shown to be sex-dependent (England et al, 1999;Hallschmid, 2021;Luberti et al, 2021;Marjan, 2023). Additional sex differences have been observed for drug ADME through ocular (Nakamura et al, 2005), intravascular (Kunio et al, 2018), and subcutaneous (Sloan, 2000) dosing paradigms; physiological considerations for these parenteral routes of administration are reviewed elsewhere (Donovan, 2005).…”