Benefits of Fenofibrate in prenatal valproic acid-induced autism spectrum disorder related phenotype in rats

Mirza, Roohi; Sharma, Bhupesh

doi:10.1016/j.brainresbull.2019.02.003

Cited by 64 publications

(39 citation statements)

References 79 publications

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“…Consistent with a PPAR-α activation, neurobehavioral and biochemical benefits in an ASD animal model were observed following administration with fenofibrate that resulted in reduced oxidative stress and inflammation in several brain regions [52]. PPAR-α is required for normal cerebral functions and its genetic ablation leads to repetitive behaviors and cognitive inflexibility in mice [118].…”

Section: Neurodevelopmental Disordersmentioning

confidence: 76%

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Hence, the strategy of targeting PPARs for their anti-inflammatory role to improve these disorders is attracting attention. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies. We reviewed running findings in support of a role for PPARs in the treatment of neurological diseases, including Alzheimer’s disease or psychiatric disorders, such as major depression. We discuss the opportunity of targeting PPARs as a future pharmacological approach to decrease neuropsychiatric symptoms at the same time that PPAR ligands resolve neuroinflammatory processes.

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Section: Neurodevelopmental Disordersmentioning

confidence: 76%

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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“…We also assessed anxious behavior in the EPM test and, as observed in other studies in adolescent and adult rats, VPA exposure was associated to increased anxiety in male rats [27,43]. However, anxiety was not rescued by FBR administration, differently from a previous report [70] showing decreased anxiety in male VPA rats receiving FBR at the same dose and for the same duration, but by gavage. The discrepancy between the two studies could be explained by the different pharmacokinetics of FBR following diet and oral administrations.…”

Section: Discussionmentioning

confidence: 88%

Targeting PPARα in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences

et al. 2020

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Background: The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor α (PPARα) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments. Methods: Male and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48-53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D 1 receptor activation, levels of expression of PPARα, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions. Results: FBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D 1 receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment. Limitations: This study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue.

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“…For example, Behavioral assessments have shown there to be significant improvements in ASD symptoms after intravenous immunoglobulin infusion in subjects via suppression of systematic inflammation (Kuo and Liu, 2018). The drugs like‐ Sulindac, minocycline, memantine, fenofibrate and fingolimod have been reported to improve social impairments, repetitive behavior, hyperlocomotion, anxiety, low exploratory activity, spatial learning and memory impairment have anti‐inflammation effects in the VPA‐treated rodent brains (Wu et al, 2017; Kumar and Sharma, 2016a, b; Mirza and Sharma, 2019). Nutrition and food extracts from hesperetin, green tea, Korean red ginseng, and AP1 (Oryza sativa and Bombyx mori extract) have also been shown to reduce ASD‐like phenotypes in VPA‐treated rodent models, possibly via an anti‐inflammatory mechanism (Khalaj et al, 2018; Morakotsriwan et al, 2016; Kuo and Liu, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…They reduced the oxidative stress via reduction of lipid peroxidation (TBARS/ MDA), total nitrite, protein oxidation, generation of reactive oxygen species with elevation of GSH, GPx, GRx, SOD, and catalase. Therefore, ASD‐related features like social deficits, repetitive/ stereotypic behavioral impairments, anxiety, hyperlocomotion, enhanced nociceptice index, poor motor co‐ordination and exploratory activity were improved by their antioxidant effects in VPA‐treated rats (Kuo and Liu, 2018; Al‐Amin et al, 2015; Khalaj et al, 2018; Morakotsriwan et al, 2016; Mirza and Sharma, 2019). Thus, antioxidants have play role to cease the exaggeration of ASD‐like features via reduction of oxidative stress and strengthen the antioxidant defense system.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of pioglitazone, a selective peroxisome proliferator‐activated receptor‐γ agonist in prenatal valproic acid‐induced behavioral and biochemical autistic like features in Wistar rats

Mirza

Sharma

2019

Intl J of Devlp Neuroscience

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in children. It is diagnosis by two main behavioral phenotypes i.e. social‐communication impairments and repetitive behavior. ASD is complex disorder with unsolved etiology due to multiple genes involvement, epigenetic mechanism and environmental factors. Valproic acid (VPA), a teratogen is known to induce characteristic features related to ASD in rodents. Numerous studies suggest the potential therapeutic effects of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) in different brain disorders. This research evaluates the utility of selective agonist of PPAR‐γ, pioglitazone in prenatal VPA induced experimental ASD symptomatology in Wistar rats. The prenatal administration of VPA has induced social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity in rats. Also, prenatal VPA‐treated rats have shown higher levels of oxidative stress (increased in thiobarbituric acid reactive species, and decreased in reduced glutathione level) and inflammation (increased in interleukin‐6, tumor necrosis factor‐alpha and decreased in interleukin‐10) in the cerebellum, brainstem and prefrontal cortex. Treatment with pioglitazone significantly attenuated the prenatal VPA‐induced social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, pioglitazone also reduced the prenatal VPA‐induced oxidative stress and neuroinflammation in aforementioned brain regions. Hence, it may be concluded that pioglitazone may provide neurobehavioral and biochemical benefits in prenatal VPA‐induced autistic phenotypes in rats.

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Benefits of Fenofibrate in prenatal valproic acid-induced autism spectrum disorder related phenotype in rats

Cited by 64 publications

References 79 publications

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Targeting PPARα in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences

Beneficial effects of pioglitazone, a selective peroxisome proliferator‐activated receptor‐γ agonist in prenatal valproic acid‐induced behavioral and biochemical autistic like features in Wistar rats

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