Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder

Kumar, Hariom; Sharma, Bhupesh

doi:10.1016/j.neuint.2015.10.007

Cited by 65 publications

(52 citation statements)

References 43 publications

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“…Anxiety is a frequent symptom displayed by autistic patients. 2 Accordingly, as previously reported, 41 , 66 , 82 , 83 the VPA-exposed rats showed an anxious phenotype in the elevated plus maze test, both during adolescence and adulthood.…”

Section: Discussionsupporting

confidence: 74%

Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid

et al. 2016

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Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communication and stereotyped/repetitive behaviors, for which no specific treatments are currently available. Prenatal exposure to valproic acid (VPA) is a known, although still underestimated, environmental risk factor for ASD. Altered endocannabinoid activity has been observed in autistic patients, and endocannabinoids are known to modulate behavioral traits that are typically affected in ASD. On this basis, we tested the hypothesis that changes in the endocannabinoid tone contribute to the altered phenotype induced by prenatal VPA exposure in rats, with focus on behavioral features that resemble the core and associated symptoms of ASD. In the course of development, VPA-exposed rats showed early deficits in social communication and discrimination, compromised sociability and social play behavior, stereotypies and increased anxiety, thus providing preclinical proof of the long-lasting deleterious effects induced by prenatal VPA exposure. At the neurochemical level, VPA-exposed rats displayed altered phosphorylation of CB1 cannabinoid receptors in different brain areas, associated with changes in anandamide metabolism from infancy to adulthood. Interestingly, enhancing anandamide signaling through inhibition of its degradation rescued the behavioral deficits displayed by VPA-exposed rats at infancy, adolescence and adulthood. This study therefore shows that abnormalities in anandamide activity may underlie the deleterious impact of environmental risk factors on ASD-relevant behaviors and that the endocannabinoid system may represent a therapeutic target for the core and associated symptoms displayed by autistic patients.

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Section: Discussionsupporting

confidence: 74%

Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid

et al. 2016

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“…Some studies, including ours, have shown that prenatal administration of VPA in rats may cause some cerebral and intestinal abnormalities similar to those in ASD patients (11)(12)(13).…”

Section: Introductionsupporting

confidence: 52%

Supplementation of Diet With Different n-3/n-6 PUFA Ratios Ameliorates Autistic Behavior, Reduces Serotonin, and Improves Intestinal Barrier Impairments in a Valproic Acid Rat Model of Autism

et al. 2020

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The implication of different dietary n-3/n-6 polyunsaturated fatty acids (PUFAs) ratios has been investigated in some neurodevelopmental disorders (including autism and depression). However, the mechanisms underlying the effects of different PUFAs ratios on the autism are still poorly understood. In the present study, a valproic acid (VPA) rat model of autism was used to study the effects of diet with different n-3/n-6 PUFA ratios on the autism, and the underlying mechanisms explored. Our results showed that rats with prenatal administration of VPA took less response time to sniff three odorants in the olfactory habituation/dishabituation tests, had lower frequency of pinning and following patterns, and had decreased hippocampal 5-hydroxytryptamine (5-HT), increased serum 5-HT and downregulated expression of tight junction protein (occludin and claudin-1) in the colon. However, supplementation of n-3/n-6 PUFAs (1:5) in the VPA treated rats ameliorated the autistic behaviors, increased hippocampal 5-HT and tight junction expression in the colon, and decreased serum 5-HT. In conclusion, dietary supplementation of n-3/n-6 PUFAs (1:5) significantly improves VPA-induced autism-like behaviors in rats, which may be, at least partially, related to the increased hippocampal 5-HT. Furthermore, this diet can increase the expression of tight junction proteins to improve intestinal barrier impairment.

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“…Given that the neonatal BBB has not yet fully formed, it is impossible to say whether these findings relate to changes at the level of the BBB in ASD at this point of development. Animal models of ASD have given some support for increased BBB permeability in ASD; in the valproic acid model of autism in rats, increases in BBB permeability (measured using Evan's Blue) have been reported [151][152][153] that can be ameliorated with treatment with the NMDA receptor agonist memantine [151], the antibiotic minocycline [152], or the melatonin receptor agonist agomelatine [153].…”

Section: Markers Of Bbb Permeability In Asdmentioning

confidence: 99%

Blood-brain barrier regulation in psychiatric disorders

Kealy

Greene

Campbell

2020

Neuroscience Letters

213

135

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The blood-brain barrier (BBB) is a dynamic interface between the peripheral blood supply and the cerebral parenchyma, controlling the transport of material to and from the brain. Tight junctions between the endothelial cells of the cerebral microvasculature limit the passage of large, negatively charged molecules via paracellular diffusion whereas transcellular transportation across the endothelial cell is controlled by a number of mechanisms including transporter proteins, endocytosis, and diffusion. Here, we review the evidence that perturbation of these processes may underlie the development of psychiatric disorders including schizophrenia, autism spectrum disorder (ASD), and affective disorders. Increased permeability of the BBB appears to be a common factor in these disorders, leading to increased infiltration of peripheral material into the brain culminating in neuroinflammation and oxidative stress. However, although there is no common mechanism underpinning BBB dysfunction even within each particular disorder, the tight junction protein claudin-5 may be a clinically relevant target given that both clinical and pre-clinical research has linked it to schizophrenia, ASD, and depression. Additionally, we discuss the clinical significance of the BBB in diagnosis (genetic markers, dynamic contrast-enhanced-magnetic resonance imaging, and blood biomarkers) and in treatment (drug delivery).

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Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder

Cited by 65 publications

References 43 publications

Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid

Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid

Supplementation of Diet With Different n-3/n-6 PUFA Ratios Ameliorates Autistic Behavior, Reduces Serotonin, and Improves Intestinal Barrier Impairments in a Valproic Acid Rat Model of Autism

Blood-brain barrier regulation in psychiatric disorders

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