Abstract
Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.
Highlights
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by persistent social interaction deficits coupled with restricted, repetitive patterns of behaviors (RRBs), that are typically diagnosed during early developmental stages [1]
Post hoc tests revealed that vehicle-treated Black and Tan BRachyury (BTBR) (63.00 ± 3.34 %) buried significantly more marbles compared to B6 mice (35.00 ± 2.45 %) with values of (F(1,8) = 7.36, p < 0.05)
The novel multiple-active H3 R and D2 receptors (D2 Rs)/D3 R antagonist ST-2223 ameliorated ASDlike restricted behaviors (RRBs) that are naturally exhibited in the BTBR mouse model of ASD
Summary
Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by persistent social interaction deficits coupled with restricted, repetitive patterns of behaviors (RRBs), that are typically diagnosed during early developmental stages [1]. RRBs refer to a broad class of responses characterized by their repetition and rigidity, including motor stereotypies, compulsions, insistence on sameness, circumscribed interests and cognitive inflexibility [5,6,7,8]. Despite its clinical significance and the fact that a great deal of research has been pursued, it has proven difficult to understand the underlying mechanisms contributing to these behaviors, RRBs in ASD are still not remediable [9,10]. Understanding the implicated neurochemical mechanisms in brain circuitry that contribute to RRBs, will be critical in developing potential pharmacotherapies [12]. Findings from several studies suggest that RRBs appear in other CNS disorders, including obsessive-compulsive disorder, Tourette syndrome (TS), and schizophrenia (SCH), all of which are comorbid with
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
