Abstract
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15 mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15 mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1 mg/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.
Highlights
Autistic spectrum disorder (ASD) is a neurodevelopmental brain disorder characterized by two major core behavioral symptoms: impairment in social interaction and communication and restricted/repetitive behavior patterns or interests, observed often before the age of three years and lasting throughout life[1,2]
DL77 (10 mg/kg) significantly improved time spent in the chamber of novel mouse (NM) over novel object (NO) in valproic acid (VPA)-exposed mice, with [F(1,12) = 13.375; P < 0.05], and the observed improvement of time spent in the chamber with NM provided by DL77 (10 mg/kg) was comparable to that shown with DOZ (1 mg/kg), with [F(1,11) = 0.060; p = 0.810] (Fig. 2A)
A statistical analysis of observed results indicated that subchronic treatment with DL77 (10 or 15 mg/kg, i.p.) exhibited a significant sociability-enhancing effect measured as time spent exploring novel mouse [F(7,43) = 4.98; P < 0.001] (Fig. 2B)
Summary
Autistic spectrum disorder (ASD) is a neurodevelopmental brain disorder characterized by two major core behavioral symptoms: impairment in social interaction and communication and restricted/repetitive behavior patterns or interests, observed often before the age of three years and lasting throughout life[1,2]. Blockade of inhibitory histamine H3 auto-receptors reinforces histaminergic neurotransmission, while antagonism of H3 hetero-receptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA)[7,9,12] Considering these findings, we evaluated the effects of the novel potent and selective H3R antagonist DL77, which has confirmed high in vitro antagonist affinity in the subnanomolar range (pKi = 8.08)[23,24,25], high in-vivo H3R antagonist central potency (ED50 = 2.1 ± 0.2 mg/kg, per os)[23,24,25], and an excellent selectivity profile (pKi (hH4R) = 4.31; pKi (hH1R) = 6.18; pKi (α2R) = 2.10)[23,24,25,26] on the ASD-like behavioral deficits in mice. The abrogative effects of the CNS-penetrant H3R agonist (R)-α-methylhistamine (RAMH), the centrally acting H1R antagonist pyrilamine (PYR), and the H2R antagonist zolantidine (ZOL) on the DL77-provided behavioral and biochemical enhancements were assessed to further explain whether brain histaminergic neurotransmission is involved in the effects provided by the H3R antagonist DL77
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