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.
Highlights
Autism spectrum disorder (ASD) is a construct used to describe individuals with a specific combination of core behavioral persistent deficits in social interactions and the presence of patterns of repetitive and restricted behaviors [1]
To comprehend our previous results observed for the dual-active compound E100 in valproic acid-induced ASD in mice and as a continuation of our research, in the present study we describe the in vivo effects of E100 (1-(7-(4-chlorophenoxy) heptyl)azepine) with balanced acetylcholine esterase (AChE) inhibitory effect (EeAChE: IC50 = 2 μM and EqBuChE: IC50 = 2 μM)
The enhancement in sociability and social novelty provided by E100 (5 mg, being the optimal dose that alleviated the assessed behavioral deficits) were completely reversed when mice were co-administered with RAM, the brain-penetrant H3R agonist
Summary
Autism spectrum disorder (ASD) is a construct used to describe individuals with a specific combination of core behavioral persistent deficits in social interactions and the presence of patterns of repetitive and restricted behaviors [1]. Studies focused on modeling ASD in rodents based on ASD-related behaviors clinically observed in individuals with ASD, such as stereotyped and repetitive behaviors and impairments in social interaction and communication. In this regard, the inbred BTBR T+ tf/J (BTBR) mice has been used as an animal model that garnered attention related to ASD because the BTBR mice exhibits behaviors consistent with the diagnostic categories for ASD, namely social impairment and obsessive/compulsive behaviors, e.g., increased self-grooming, marble burying and disturbed anxiety levels [6,7,8]. Alterations in the levels of nAChRs were observed in numerous areas of the brain including neocortex, thalamus, striatum and cerebellum of ASD individuals, with the central abnormality being the diminishment of muscarinic receptors (M1 subtype) [10,11]
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