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

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.

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

“…Contrary, CUR (25, 50, and 100 mg/kg) were capable of restoring the levels of CAT levels in the cerebellum, but failed to alter the levels of SOD in the hippocampus. The results observed on the levels of oxidative stress markers are in harmony with numerous previous preclinical reports from our group and other research groups that investigated the effects of synthetic ligands modulating brain ACh levels on oxidative stress in the brains of different rodent models [53][54][55][56][57]. Also, the results observed for CUR are in harmony with a previous preclinical study in which CUR was found to mitigate the disturbed levels of IFN-γ, serotonin, glutamine, reduced glutathione, glutathione S-transferase, lipid peroxidase with an increase in CYP450, IL-6, glutamate, and oxidized glutathione in valproate-induced ASD in rats [58].…”

“…injections of MLA (1 µg/kg). Doses of CUR, DOZ, and MLA were selected according to previous experimental protocols C57 mice as well as BTBR mice [ 10 , 38 , 48 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. In these studies, a dose range of 15–125 mg/kg was used to assess several in vivo effects of CUR in mice.…”

“…In addition, and in numerous previous studies from our group, DOZ (1 mg/kg, i.p.) was proven to show enhancing effects of cognitive functions of BTBR mice [ 9 , 10 , 48 , 53 , 55 , 56 , 57 ]. Therefore, a dose of 1 mg/kg of DOZ was selected in the current in vivo behavioral assessments.…”

“…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].…”