Abstract
The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer’s disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: Ki = 203 nM) and balanced AChE inhibitory effect (EeAChE: IC50 = 2 µM and EqBuChE: IC50 = 2 µM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all p < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all p < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels (p < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all p < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice (p < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours.
Highlights
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder with a large population prevalence, characterized by impairments in social interaction and restricted/repetitive behavioral pattern or interest [1,2]
As observed in the Tukey post hoc analyses, valproic acid (VPA) mice exhibited significantly lower sociability expressed as sociability index (SI) when compared to saline-exposed control mice (CNT), with SIs of (−0.07 ± 0.05) and (0.40 ± 0.07), respectively (p < 0.01) (Figure 2A)
The results revealed that the enhancement in SI observed with E100 (10 mg/kg, SI = 0.44 ± 0.08) was statistically comparable to that shown with DOZ (1 mg/kg, SI = 0.39 ± 0.07, p = 0.99) (Figure 2A)
Summary
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder with a large population prevalence, characterized by impairments in social interaction and restricted/repetitive behavioral pattern or interest [1,2]. The brain cholinergic neurotransmitter system with ACh has an essential role in controlling ASD-related behavioral features including attention [19], cognitive flexibility [20], social interaction [21], and stereotypical behaviors [9,16,18,22]. Famotidine (a histamine H2R antagonist) was projected to be a possible treatment for ASD children [12], since famotidine was revealed to alleviate sociability deficits in a patient with schizophrenia [13], a brain disorder that shares various genetic factors and symptoms with ASD [14,15]. Antagonism of histamine H3Rs was found to reduce social behavior deficits in rodents exposed to phencyclidine, signifying the promising potential use of H3R antagonist in the therapeutic management of ASD [31,32]. FEFEi1i1gg00uu00rraeeann1d1d..iCCninhhveeivtmmirtoriiccodaaalldtssaatttrrwauuicwcthttuuitrrrheeegrooaerffgdttahhtroeedhddtHuoua1ah-ll-,H-aahc1cHtt-ii,3nn-hgg,Hahhn3uud-,mmhaHaannnd4RHHh,H33ERRe4AR((hCh,HHhEE3e3AR,Ra)C)naahdnnEEtt,aaqgagBnooudnnCiisEshttEqaaB.nnau,ddbC,cAhABECCi.nhhadE,Ebi,cniingnBhhianiisbbdsiiaittnyoogsrr tdaposersesdacveyritioseburtemosdliydnneed=teaesffir3cmr[n5iibin9tey]e.dtadonffAHi=nC13i-th,y[E5Ht9:o3]A.-H,cAae1Cnt-yd,hlHEcHh:34oA-R,licasnenewtydeelscrHtehe4oprRlaeissnrefewo; reEemsert;eeeerdplaeeiscnretf;rdoiEricffmee;eeeerldel;enecitntlByriudceCixfefhpeeElrr;ee:EsnBsqteul:dyteyqcereuxylpillncsrheeaoss[sl6pie3nrd–ee6svc5teieo]l.rlusassaleys; Eq: equine [63,64,65]
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