Elsevier

Life Sciences

Volume 141, 15 November 2015, Pages 156-169
Life Sciences

Neuropsychopharmacotherapeutic efficacy of curcumin in experimental paradigm of autism spectrum disorders

https://doi.org/10.1016/j.lfs.2015.09.012Get rights and content

Abstract

Aim

Neuroinflammatory response triggered by the stimulation of matrix metalloproteinases plays a pivotal role in the development of autistic phenotype. MMPs stimulate inflammatory cytokines release along with mitochondrial deficits that ultimately lead to neuronal dysfunction and precipitate autistic symptoms. The aim of the present study was to explore the neuropsychopharmacotherapeutic efficacy of curcumin in the experimental paradigm of autism spectrum disorders.

Materials and methods

1 M propanoic acid (4 μl) was infused over 10 min into the anterior portion of the caudoputamen to induce autistic behavior in rats. Curcumin (50, 100 and 200 mg/kg) was administered per orally starting from 2nd day of surgery and continued up to 28th day. Rats were tested for various neurobehavioural paradigms like social interaction, stereotypy, locomotor activity, anxiety, novelty, depression, spatial learning and memory as well as for repetitive and pervasive behavior. In addition, biochemical tests for oxidative stress, mitochondrial complexes, TNF-α and MMP-9 were also carried out.

Key findings

Intracerebroventricular injection of propanoic acid produced neurological, sensory, behavioral, biochemical and molecular deficits which were assessed as endophenotype of autism spectrum disorders. Regular treatment with curcumin for four weeks significantly and dose dependently restored neurological, behavioral, biochemical and molecular changes associated with autistic phenotype in rats.

Significance

The major finding of the study is that curcumin restored the core and associated symptoms of autistic phenotype by suppressing oxidative-nitrosative stress, mitochondrial dysfunction, TNF-α and MMP-9 in PPA-induced autism in rats. Therefore, curcumin can be developed as a potential neuropsychopharmacotherapeutic adjunct for autism spectrum disorders (ASD).

Graphical abstract

Curcumin treatment ameliorates the various neurobehavioural, biochemical and molecular deficits induced by PPA in the rat model of ASD.

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Introduction

Autism spectrum disorders (ASD) is a complex syndrome which is characterized by a heterogeneous group of neuropsychiatric disorders that affects the brain in the developmental stage [70]. US Center for Disease Control & Prevention (CDC) has reported the prevalence of ASD to be 1 in 68 children in 2014 as compared to 1 in 88 in 2010. Autism Society of India has reported the prevalence rate of autism to be 1 in 250. Currently 10 million people are suffering from ASD in India. ASD shows significant skewness with respect to occurrence in boys having a sex ratio of 4:1 [19], [27], [62]. ASD is characterized by core symptoms like loss of social interaction, non-social approach, impairment of communication as well as by associated symptoms like irritable nature, anxiety, aggression, epilepsy and sensory processing disorder [5], [25], [70].

Neuroinflammatory response triggered by the stimulation of matrix metalloproteinases plays a pivotal role in the development of autistic phenotype. MMPs stimulate inflammatory cytokines release along with mitochondrial deficits that ultimately lead to neuronal dysfunction and precipitate autistic symptoms [51], [58]. For the past two decades the scientific community is focusing on the exploration of neuropsychopharmacotherapeutic potential of phytochemicals in the plethora of human ailments. Curcumin (diferuloyl methane) is the primary curcuminoid which is present in the Indian spice turmeric (Curcuma longa) and is regarded as “Indian Solid Gold”. Its several pharmacological activities like being anti-inflammatory, antioxidant, anti-carcinogenic and neuroprotective have been highlighted in various studies [2], [15], [30], [34], [46], [61], [64], [71], [74], [81], [56]. With this background, the current study was designed to explore neuropsychopharmacotherapeutic potential of curcumin against PPA-induced autistic behavior in Sprague–Dawley rats.

Section snippets

Animals

Male Sprague–Dawley rats (250–280 g), 3–4 months old, bred in the Central Animal House Facility of the Panjab University, Chandigarh (India) were used. The animals were housed under standard laboratory conditions, maintained on a 12 h light and dark cycle and had free access to food (Ashirwad Industries, Chandigarh, India) and water. The experimental protocols were approved by the Institutional Animal Ethics Committee of the Panjab University, Chandigarh, and conducted according to the Indian

Effect of curcumin on the time spent in non-social and social interaction in reciprocal social interaction test

The time spent in non-social interaction like self grooming and arena exploration was significantly increased after the administration of PPA (450.8 ± 10 s) as compared to the control group (50.0 ± 20 s), sodium acetate control group (98.0 ± 15 s), PBS control group (99.3 ± 30.0 s) and propanol group (95.3 ± 35.0 s) [F7,32 = 46.30 (p < 0.0001)]. There was significant and dose dependent reduction in the non-social interaction time after regular administration of curcumin (50, 100 and 200 mg/kg), as compared to the

Discussion

Propanoic acid (PPA) serves as an important link between dietary metabolic products and genetic predisposition for development of clinical pathology of ASD [4], [66]. PPA induced ASD model has a clinical significance because short chain fatty acids (SCFAs) such as PPA are produced as a result of breakdown of dietary carbohydrates and amino acids [24] by many gut bacteria such as Clostridia and Desulfovibrio. These bacteria have also been proposed as infectious causes of ASDs [18]. MacFabe et

Statement of interest

There is no conflict of interest.

Acknowledgments

Research grants sanctioned by SERB, Department of Science & Technology (grant no SB/FT/LS-284/2012), All India Council of Technical Education (11-25/RIFD/CAYT/POL-II/2013-14) and University Grants Commission (20-29(12)/2012(BSR), New Delhi to Dr. Anurag Kuhad are gratefully acknowledged. Senior Research Fellowship sanctioned by Indian Council of Medical Research (45/13/2014-Nan/BMS), New Delhi to Ms. Ranjana Bhandari is also gratefully acknowledged.

References (81)

  • K. Horvath et al.

    Gastrointestinal abnormalities in children with autistic disorder

    J. Pediatr.

    (1999)
  • L.L. Hurley et al.

    Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF

    Behav. Brain Res.

    (2013)
  • G. Karvat et al.

    Systematic autistic-like behavioural phenotyping of 4 mouse strains using a novel wheel-running assay

    Behav. Brain Res.

    (2012)
  • T.E. King

    Preparation of succinate dehydrogenase and reconstitution of succinate oxidase

    Methods Enzymol.

    (1967)
  • T.E. King et al.

    Preparations and properties of soluble NADH dehydrogenases from cardiac muscle

    Methods Enzymol.

    (1967)
  • Y. Kono

    Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase

    Arch. Biochem. Biophys.

    (1978)
  • A. Kuhad et al.

    Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences

    Eur. J. Pharmacol.

    (2007)
  • X. Li et al.

    Elevated immune response in the brain of autistic patients

    J. Neuroimmunol.

    (2009)
  • D.F. MacFabe et al.

    Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders

    Behav. Brain Res.

    (2007)
  • J. Murray et al.

    Oxidative damage to mitochondrial complex I due to peroxynitrite

    J. Biol. Chem.

    (2003)
  • L. Palmieri et al.

    Mitochondrial dysfunction in autism spectrum disorders: cause or effect?

    Biochim. Biophys. Acta

    (2010)
  • L.F. Pettenuzzo et al.

    Differential inhibitory effects of methylmalonic acid on respiratory chain complex activities in rat tissues

    Int. J. Dev. Neurosci.

    (2006)
  • V. Raghavendra et al.

    Brain renin angiotensin system(RAS) in stress-induced analgesia and impaired retention

    Peptides

    (1999)
  • A.K. Sachdeva et al.

    Epigallocatechin gallate ameliorates behavioral and biochemical deficits in rat model of load-induced chronic fatigue syndrome

    Brain Res. Bull.

    (2011)
  • K. Saja et al.

    Anti-inflammatory effect of curcumin involves downregulation of MMP-9 in blood mononuclear cells

    Int. J. Immunopharmacol.

    (2007)
  • S.R. Shultz et al.

    Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long–Evans rat: further development of a rodent model of autism

    Behav. Brain Res.

    (2009)
  • M. Tuzcu et al.

    Effect of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats

    Eur. J. Pharmacol.

    (2006)
  • Y. Xu et al.

    Curcumin reverses impaired cognition and neuronal plasticity induced by chronic stress

    Neuropharmacology

    (2009)
  • Y. Xu et al.

    Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats

    Pharmacol. Biochem. Behav.

    (2005)
  • M.W. Abdallah et al.

    Matrix metalloproteinases in autism spectrum disorders

    J. Mol. Psychiatry

    (2013)
  • B.B. Aggarwal et al.

    Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers

    Br. J. Pharmacol.

    (2013)
  • S.S. Agrawal et al.

    Neurodegenerative shielding by curcumin and its derivatives on brain lesions induced by 6-OHDA model of Parkinson's disease in albino wistar rats

    Cardiovasc. Psychiatry Neurol.

    (2012)
  • A.M. Aldbass et al.

    Protective and therapeutic potency of N-acetyl-cysteine on propionic acid-induced biochemical autistic features in rat

    J. Neuroinflammation

    (2013)
  • American Psychiatric Association WDC

    Diagnostic and Statistical Manual of Mental Disorders (DSM-V)

  • M. Antunes et al.

    The novel object recognition memory: neurobiology, test procedure, and its modifications

    Cogn. Process.

    (2012)
  • S.B. Berman et al.

    Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease

    J. Neurochem.

    (1999)
  • J. Bouayed et al.

    Oxidative stress and anxiety: relationship and cellular pathways

    Oxidative Med. Cell. Longev.

    (2009)
  • R.J. Chandler et al.

    Mitochondrial dysfunction in mut methylmalonic acidemia

    FASEB J.

    (2009)
  • A. Claiborne

    Catalase activity

  • G.M. Cole et al.

    Neuroprotective effects of curcumin

    Adv. Exp. Med. Biol.

    (2007)
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