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Protective Effect of Spermidine Against Excitotoxic Neuronal Death Induced by Quinolinic Acid in Rats: Possible Neurotransmitters and Neuroinflammatory Mechanism

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Abstract

Huntington disease is hyperkinetic movement disorder characterized by selective and immense degradation of GABAergic medium spiny neurons in striatum. Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as excitotoxicity, ATP depletion, oxidative stress, neuroinflammation, as well as selective GABAergic neuronal loss. Therefore, we investigated spermidine, an endogenous molecule with free radical scavenging, anti-inflammatory, and N-methyl-d-aspartate receptor antagonistic properties, for its beneficial potential if any, in QA-induced Huntington’s like symptoms in rats. Rats were administered with QA (200 nmol/2 µl saline) bilaterally on 0 day. Spermidine (5 and 10 mg/kg, p.o.) was administered for 21 days once a day. Behavioral parameters (body weight, locomotor activity, grip strength, and narrow beam walk) observations were done on 1st, 7th, 14th, and 21st day after QA treatment. On 21st day, animals were sacrificed and rat striatum was isolated for biochemical (LPO, GSH, Nitrite), neuroinflammation (TNF-α, IL-1β, and IL-6), and neurochemical analysis (GABA, glutamate, dopamine, norepinephrine, serotonin, DOPAC, HVA, 5-HIAA, adenosine, adenine, hypoxanthine, and inosine). QA treatment significantly altered body weight, locomotor activity, motor coordination, oxidative defense (increased LPO, nitrite, and decreased GSH), pro-inflammatory levels (TNF-α, IL-6 and IL-1β), GABA, glutamate, catecholamines level (norepinephrine, dopamine, and serotonin and their metabolites), and purines level (adenosine, inosine, and hypoxanthine). Spermidine (5 and 10 mg/kg, p.o.) significantly attenuated these alterations in body weight, motor impairments, oxidative stress, neuroinflammatory markers, GABA, glutamate, catecholamines, adenosine, and their metabolites levels in striatum. The neuroprotective effect of spermidine against QA-induced excitotoxic cell death is attributed to its antioxidant, N-methyl-d-aspartate receptor antagonistic, anti-inflammatory properties, and prevention of neurotransmitters alteration in striatum.

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Abbreviations

QA:

Quinolinic acid

HD:

Huntington’s disease

LPO:

Lipid peroxidation

MDA:

Malondialdehyde

MSNs:

Medium spiny neurons

NF-кB:

Nuclear factor-kappa beta

NMDA:

N-methyl-d-aspartate

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor-alpha

IL-1β:

Interleukin-1 βeta

DOPAC:

3,4-Dihydroxyphenylacetic acid

HVA:

Homovanillic acid

5-HIAA:

5-Hydroxy 3-indole acetic acid

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Acknowledgments

Authors are thankful to Science and Engineering Board (SERB), Department of Science and Technology, Govt. of India, New Delhi for providing financial assistance under Fast Track Scheme (DST-SERB-FTYS) to Dr. Puneet Kumar. The Junior Research Fellowship to Mr. Sumit Jamwal is also highly acknowledged.

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Authors and Affiliations

  1. Department of Pharmacology, I.S.F College of Pharmacy, Ferozepur GT Road, Ghal Kalan, Moga, 142001, Punjab, India

    Sumit Jamwal, Shamsher Singh, Navneet Kaur & Puneet Kumar

  2. Punjab Technical University, Jalandhar, India

    Sumit Jamwal & Shamsher Singh

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  1. Sumit Jamwal
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  2. Shamsher Singh
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  3. Navneet Kaur
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  4. Puneet Kumar
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Correspondence to Puneet Kumar.

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Jamwal, S., Singh, S., Kaur, N. et al. Protective Effect of Spermidine Against Excitotoxic Neuronal Death Induced by Quinolinic Acid in Rats: Possible Neurotransmitters and Neuroinflammatory Mechanism. Neurotox Res 28, 171–184 (2015). https://doi.org/10.1007/s12640-015-9535-y

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