Simultaneous Blockade of Histamine H3 Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism

Abstract

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H3R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed.

The Multi-Targeting Ligand ST-2223 with Histamine H3 Receptor and Dopamine D2/D3 Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice

“…Moreover, systemic administration with the most promising dose of ST-2223 (5 mg/kg), ARP (1 mg/kg) or MEM (5 mg/kg) showed a significant reduction in MDA, as well as a significant elevation in GSH, SOD, and CAT in different areas of the brain. The results observed on the levels of oxidative stress markers are in agreement with several previous reports from our group and other research groups that investigated the effects of H3R antagonists on oxidative stress in the brains of different rodent models [79,[82][83][84][85][86]. Accordingly, previous reports showed that imidazole-based H3R antagonists, including clobenpropit and ciproxifan, mitigated several oxidative stress markers (e.g., MDA and GSH) in amphetamine-or dizocilpine-augmented oxidative stress in a preclinical mouse model of schizophrenia, suggesting the protective effect of H3R antagonists in such disease conditions [87][88][89].…”

Curcumin Potentiates α7 Nicotinic Acetylcholine Receptors and Alleviates Autistic-Like Social Deficits and Brain Oxidative Stress Status in Mice

“…Three Chamber Paradigm (TCP) TC test was performed according to previously described protocols [48,53,56,57,62,63]. Briefly, the cage consisted of three chambers, wherein the center chamber had two square shaped openings with doors, which provided access to left and right chambers.…”

“…The hippocampus was homogenized in a KCl buffer (Tris-HCl, 10 mM NaCl, 140 mM KCl, 300 mM EDTA, and 0.5% of 1 mM Triton-X-100) at pH 8.0 supplemented with protease and phosphatase inhibitor. The homogenate was centrifuged at 10,000 rcf for 30 min at 4 • C. The supernatant was used according to previously described experimental protocols from our laboratories for the estimation of oxidative stress markers, namely catalase (CAT) and superoxide dismutase (SOD) [48,49,53,56].…”

Histamine, Neuroinflammation and Neurodevelopment: A Review

“…However, other H 3 receptor antagonists/inverse agonists are in development for other indications relevant to those with NDDs. Most these have focused on the modulating restricted and repetitive behaviors or aggression or at improving cognition and sociability in animal models (Orsetti et al, 2001;Galici et al, 2009;Southam et al, 2009;Esbenshade et al, 2012;Brown et al, 2013;Baronio et al, 2015;Eissa et al, 2018aEissa et al, ,b, 2020b. For example, a clinical trial with the H 3 receptor antagonist, AZD5213, for people with TS showed a 2-3 point reduction in Total Tic Severity Score Compared to placebo (Clinical Trials.Gov, 2016).…”