Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice.

Abstract

Parkinson's disease (PD) is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic) neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS) such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS), a paradigm developed as an animal model of depression in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt.) with probenecid (250 mg/kg, s.c.) (MPTP/p) induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks) of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor) impairments, levels and expressions of dopamine (DA), serotonin (5-HT), DAergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporters-2 (VMAT 2) and α-synuclein in nigrostriatal (striatum (ST) and substantia nigra (SN)) and extra-nigrostriatal (hippocampus, cortex and cerebellum) tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.

• Authors: Udaiyappan Janakiraman, Thamilarasan Manivasagam, Arokiasamy Justin Thenmozhi, Musthafa Mohamed Essa, Rajamani Barathidasan, Chidambaram SaravanaBabu, Gilles J Guillemin, Mohammed A S Khan
• Journal: PloS one (PLoS One) Vol. 11 Issue 1 Pg. e0146671 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26765842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Slc18a2 protein, mouse
• Vesicular Monoamine Transport Proteins
• alpha-Synuclein
• Serotonin
• Tyrosine 3-Monooxygenase
• Probenecid
• Dopamine

Topics

• Animals
• Behavior, Animal
• Brain (metabolism, physiology)
• Dopamine (metabolism)
• Locomotion
• MPTP Poisoning (complications, metabolism, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Organ Specificity
• Probenecid (toxicity)
• Serotonin (metabolism)
• Stress, Psychological (complications, metabolism, physiopathology)
• Tyrosine 3-Monooxygenase (metabolism)
• Vesicular Monoamine Transport Proteins (metabolism)
• alpha-Synuclein (metabolism)