Pharmacological intervention of behavioural traits and brain histopathology of prenatal valproic acid-induced mouse model of autism – PubMed Black Hawk Supplements

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Autism spectrum disorder (ASD) is one of the leading causes of distorted social communication, impaired speech, hyperactivity, anxiety, and stereotyped repetitive behaviour. The aetiology of ASD is complex; therefore, multiple drugs have been suggested to manage the symptoms. Studies with histamine H3 receptor (H3R) blockers and acetylcholinesterase (AchE) blockers are considered potential therapeutic agents for the management of various cognitive impairments. Therefore, the aim of this study…
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Pharmacological intervention of behavioural traits and brain histopathology of prenatal valproic acid-induced mouse model of autism - PubMed

Pharmacological intervention of behavioural traits and brain histopathology of prenatal valproic acid-induced mouse model of autism

Sharmind Neelotpol et al. PLoS One. .

Abstract

Autism spectrum disorder (ASD) is one of the leading causes of distorted social communication, impaired speech, hyperactivity, anxiety, and stereotyped repetitive behaviour. The aetiology of ASD is complex; therefore, multiple drugs have been suggested to manage the symptoms. Studies with histamine H3 receptor (H3R) blockers and acetylcholinesterase (AchE) blockers are considered potential therapeutic agents for the management of various cognitive impairments. Therefore, the aim of this study was to evaluate the neuro-behavioural effects of Betahistine, an H3R antagonist, and Donepezil, an acetylcholinesterase inhibitor on Swiss albino mouse model of autism. The mice were intraperitoneally injected with valproic acid (VPA) on the embryonic 12.5th day to induce autism-like symptoms in their offspring. This induced autism-like symptoms persists throughout the life. After administration of different experimental doses, various locomotor tests: Open Field, Hole-Board, Hole Cross and behavioural tests by Y-Maze Spontaneous Alternation and histopathology of brain were performed and compared with the control and negative control (NC1) groups of mice. The behavioural Y-Maze test exhibits significant improvement (p <0.01) on the short term memory of the test subjects upon administration of lower dose of Betahistine along with MAO-B inhibitor Rasagiline once compared with the NC1 group (VPA-exposed mice). Furthermore, the tests showed significant reduction in locomotion in line crossing (p <0.05), rearing (p <0.001) of the Open Field Test, and the Hole Cross Test (p <0.01) with administration of higher dose of Betahistine. Both of these effects were observed upon administration of acetylcholinesterase inhibitor, Donepezil. Brain-histopathology showed lower neuronal loss and degeneration in the treated groups of mice in comparison with the NC1 VPA-exposed mice. Administration of Betahistine and Rasagiline ameliorates symptoms like memory deficit and hyperactivity, proving their therapeutic effects. The effects found are dose dependent. The findings suggest that H3R might be a viable target for the treatment of ASD.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Schematic diagram of doses, and time schedule for the behavioural and locomotor tests in healthy and VPA-induced mice.

Pregnant mice were given VPA (600 mg/kg, i.p.) on embryonic day 12.5 (E12.5). Drugs were given by oral gavage from postnatal day 44 (P44) until postnatal day 64 (P64) for a total of 21 days. Behavioural tests were conducted starting from P51. OFT: Open Field Test; HBT: Hole Board Test; HCT: Hole Cross Test.

Fig 2
Fig 2. Graphical representation of spontaneous alternation percentage in Y-maze test (Mean±SE).

(A) Spontaneous alternation percentage in Y-maze test of Betahistine, compared to negative control group 1. (B) Spontaneous alternation percentage in Y-maze test of Donepezil, compared to negative control group 1. (*p < 0.05, **p < 0.01 and ***p < 0.001). When compared with the control group, the treated groups did not show any significant difference (indicates as n.s i.e. non-significant).

Fig 3
Fig 3. Graphical representation of Open-field test (Mean±SE).

(A&B) Line crossing test of Betahistine and Donepezil, respectively. (C&D) Rearing test of Betahistine and Donepezil, respectively. (E&F) Central area frequency test of Betahistine and Donepezil, respectively. The following symbols: *, **, *** and Δ, ΔΔ, ΔΔΔ represents level of significance (p-values) at 5%, 1% and 0.1% level, when compared the treated groups with negative control 1 group and control group, respectively. n.s indicates non-significant.

Fig 4
Fig 4. Graphical representation of Hole-board test (Mean±SE).

(A&B) Line cross test of Betahistine and Donepezil, respecgively. (C&D) Head Dipping test of Betahistine and Donepezil, respectively. The following symbols: *, **, *** and Δ, ΔΔ, ΔΔΔ represents level of significance (p-values) at 5%, 1% and 0.1% level, when compared the treated groups with negative control 1 group and control group, respectively; n.s indicates non-significant.

Fig 5
Fig 5. Graphical representation of Hole-cross test (Mean±SE).

(A&B) Hole-cross test of Betahistine and Donepezil, respectively. The following symbols: *, **, *** and Δ, ΔΔ, ΔΔΔ represents level of significance (p-values) at 5%, 1% and 0.1% level, when compared the treated groups with negative control 1 group and control group, respectively. n.s indicates non-significant.

Fig 6
Fig 6. Histopathology of the mouse brain.

(A) Unremarkable microscopic observation in the control group (100X). (B) Neuron degeneration was observed in the negative control 1 group (40X). (C) Mild gliosis, neuronal loss in cornue ammonis, and dilated ventricles were observed in treated group 1 (40X). (D) Neuronal degeneration, a few apoptotic cells, and neuronal loss were observed in Treated group 2 (100X). (E) Thinning of hippocampus, degenerated neuron and moderate gliosis were observed in treated group 3 (100X). (F) Thinning of hippocampus, degenerated neuron and moderate gliosis were observed in treated group 4 (400X). (G) Degenerated neurons in amygdala and neuronal loss in the cortex were observed in treated group 5 (400X). (H) Unremarkable microscopic observation in negative control 2 (40X).

References

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Pharmacological intervention of behavioural traits and brain histopathology of prenatal valproic acid-induced mouse model of autism – PubMed