The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of diferent brain disorders, e.g., cognitive impairments. Therefore, the efects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited signifcantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15mg/kg, i.p.). VPA-exposed mice presented a signifcantly higher percentage of buried marbles in MBT and shredded nestlet signifcantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a signifcantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1mg/kg, i.p.) signifcantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinfammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an efective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data