Histamine H3 receptor antagonism modulates autism-like hyperactivity but not repetitive behaviors in BTBR T+Itpr3tf/J inbred mice

Background: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain. Methods: Different doses of H3 receptor agonists (i.e., (R)-α-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts. Results: The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereo-typic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors. Conclusions: Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels

THE ROLE OF HISTAMINE H3 RECEPTOR ANTAGONISTS IN MODULATING AUTISTIC BEHAVIORS AND ALTERED CENTRAL INFLAMMATORY RESPONSES IN DIFFERENT MOUSE MODELS OF AUTISM SPECTRUM DISORDER

Autistic spectrum disorder (ASD) represents a neurodevelopmental disorder characterized by impairment of social communication and restricted/repetitive behavior patterns or interests. Brain histamine and acetylcholine play a crucial role in cognitive functions. Considering this, the effects of systemic sub-chronic treatment with H3R antagonist DL77 (5, 10, or 15 mg/kg) on autistic-like behavioral parameters, oxidative stress, and neuroinflammation in male Tuck-Ordinary (TO) and C57BL/6 (C57) mice, prenatally exposed to valproic acid (VPA, 500 mg/kg), were investigated. Furthermore, the effects of dual-active H3R antagonist and balanced acetylcholinesterase inhibitor E100 (5, 10, or 15 mg/kg) on autistic-associated abnormalities of VPA- exposed male C57 mice, as well as BTBR T+tf/J (BTBR) mice, were assessed. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed TO and C57 mice pretreated with DL77 (10 mg/kg) or (15 mg/kg), respectively. Moreover, the same doses of DL77 attenuated repetitive/compulsive behaviors of both strains of mice, without appreciable effects on disturbed anxiety and hyperactivity when compared to the reference drug donepezil (1 mg/kg). The amelioration in autistic-like phenotypes by DL77 was accompanied by the attenuation of oxidative stress by increasing glutathione and decreasing malondialdehyde levels, and attenuation of proinflammatory cytokines interleukin-1β, interleukin-6 and tumor necrosis factor-α in brain tissues from VPA-exposed mice. Comparing the results observed for DL77, the dual-active E100 (10 mg/kg) showed significantly higher improvement of autistic behavioral alterations in VPA-exposed C57 mice, and significantly palliated disturbed anxiety levels. In addition, E100 attenuated several pro-inflammatory cytokines and inflammatory mediators through the suppression of upregulated NF-κB signaling. Immunofluorescence analysis showed a significant reduction in ionized calcium-binding adaptor molecule-1 increased expression in VPA-exposed C57 mice by E100, demonstrating attenuation of activated microglia. Similarly, oxidative stress status was also mitigated by E100 in brain tissues. The promising effects of E100 on autistic features in C57 mice were further complemented with the results following treatment with E100 (5 mg/kg) in BTBR mice as an idiopathic model of ASD. These results evidence that simultaneous modulation of brain histaminergic and cholinergic Neurotransmissions may have therapeutic efficacy for core symptoms of ASD. Further preclinical investigations are still necessary to corroborate and expand these observed data

CANAGLIFLOZIN AMELIORATES AUTISTIC-LIKE FEATURES AND MITIGATES BRAIN OXIDATIVE STRESS LEVELS IN VALPROIC ACID-INDUCED AUTISM IN RATS

Autism spectrum disorder (ASD) is a neurodevelopmental disease with a substantially increasing incidence rate. It is mainly characterized by repetitive behavior, intellectual difficulties, social communication and interactions deficits. Many medications, dietary supplements, and behavioral treatments have been recommended for ASD management, however, there is no cure yet. Recent studies have examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in neurodevelopmental diseases, based on their proved anti-inflammatory and antioxidant effects. The main objective of this study is to assess the ability of canagliflozin in improving the behavioural characteristics of autistic rats and investigate the efficacy of canagliflozin in reducing oxidative stress and acetylcholinesterase activity (AChE) in VPA-exposed rats. Moreover, compare male and female autistic wistar rats with regard to treatment response. ASD was induced by prenatal exposure to 500 mg/kg of Intraperitoneal (i.p.) valproic acid (VPA) at 12.5 gestational day (GD), then autistic rats were treated with 20, 50, or 100 mg/kg of (i.p.) canagliflozin for 29 days. Additionally, rats with VPA-induced ASD were subjected to behavioral assessment at post-natal day 51 (PND) including open field, marble burying, and nestlet shredding tests to examine their repetitive-compulsory behavior and anxiety. After behavioral assessment, rats went through perfusion, and then hippocampus, prefrontal cortex, and cerebellum were extracted to undergo biochemical assays. Canagliflozin achieved substantial ameliorating effects on ASD-like behaviors at various doses. Also, 20, 50, and 100 mg/kg of canagliflozin significantly increased antioxidants levels including GSH, SOD, CAT in different brain regions, as well as decreased MDA and AChE activity in the brain of autistic rats. This study, for the first time, proposed repurposing the use of canagliflozin in ASD management. Moreover, the results stated promising therapeutic effects, that were noticeable in both genders