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Neuroprotection by valproic acid in an intrastriatal rotenone model of Parkinson's disease.
Neuroscience. 2014 May 16; 267:114-21.N

Abstract

Rotenone, which is used as a pesticide and insecticide, has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of dopaminergic neurons within the substantia nigra and striatum, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of valproic acid (VPA), which is known to upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle or VPA at a dose of 4mg/mL in drinking water. The right striatum was lesioned by infusion of rotenone at three sites (2μg/site) along its rostro-caudal axis. A forelimb asymmetry (cylinder) test indicated a significant (p<0.01) decrease in use of the contralateral forelimb in rotenone-lesioned animals, in the third week post-lesioning, which was abolished by VPA treatment. Similarly, a significant (p<0.01) and persistent increase in use of the ipsilateral forelimb in lesioned animals over the 4weeks of testing, was not seen in animals treated with VPA. Results of the asymmetry test illustrate that intrastriatal infusion of rotenone causes contralateral motor dysfunction, which is blocked by VPA. The significant increase in ipsilateral forelimb use has not been documented previously, and presumably represents a compensatory response in lesioned animals. Six weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. VPA treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counting indicated a significant (p<0.05) decrease in tyrosine hydroxylase-positive dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, this loss of dopamine neurons in rotenone-lesioned animals, was blocked by chronic VPA treatment. These findings strongly support the therapeutic potential of VPA in Parkinson's disease.

Authors+Show Affiliations

Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. Electronic address: niles@mcmaster.ca.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24613722

Citation

Carriere, C H., et al. "Neuroprotection By Valproic Acid in an Intrastriatal Rotenone Model of Parkinson's Disease." Neuroscience, vol. 267, 2014, pp. 114-21.
Carriere CH, Kang NH, Niles LP. Neuroprotection by valproic acid in an intrastriatal rotenone model of Parkinson's disease. Neuroscience. 2014;267:114-21.
Carriere, C. H., Kang, N. H., & Niles, L. P. (2014). Neuroprotection by valproic acid in an intrastriatal rotenone model of Parkinson's disease. Neuroscience, 267, 114-21. https://doi.org/10.1016/j.neuroscience.2014.02.028
Carriere CH, Kang NH, Niles LP. Neuroprotection By Valproic Acid in an Intrastriatal Rotenone Model of Parkinson's Disease. Neuroscience. 2014 May 16;267:114-21. PubMed PMID: 24613722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotection by valproic acid in an intrastriatal rotenone model of Parkinson's disease. AU - Carriere,C H, AU - Kang,N H, AU - Niles,L P, Y1 - 2014/03/06/ PY - 2013/10/03/received PY - 2014/02/15/revised PY - 2014/02/20/accepted PY - 2014/3/12/entrez PY - 2014/3/13/pubmed PY - 2014/12/15/medline KW - Parkinson’s disease KW - intrastriatal KW - neuroprotection KW - rotenone KW - valproic acid SP - 114 EP - 21 JF - Neuroscience JO - Neuroscience VL - 267 N2 - Rotenone, which is used as a pesticide and insecticide, has been shown to cause systemic inhibition of mitochondrial complex I activity, with consequent degeneration of dopaminergic neurons within the substantia nigra and striatum, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of valproic acid (VPA), which is known to upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle or VPA at a dose of 4mg/mL in drinking water. The right striatum was lesioned by infusion of rotenone at three sites (2μg/site) along its rostro-caudal axis. A forelimb asymmetry (cylinder) test indicated a significant (p<0.01) decrease in use of the contralateral forelimb in rotenone-lesioned animals, in the third week post-lesioning, which was abolished by VPA treatment. Similarly, a significant (p<0.01) and persistent increase in use of the ipsilateral forelimb in lesioned animals over the 4weeks of testing, was not seen in animals treated with VPA. Results of the asymmetry test illustrate that intrastriatal infusion of rotenone causes contralateral motor dysfunction, which is blocked by VPA. The significant increase in ipsilateral forelimb use has not been documented previously, and presumably represents a compensatory response in lesioned animals. Six weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. VPA treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counting indicated a significant (p<0.05) decrease in tyrosine hydroxylase-positive dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, this loss of dopamine neurons in rotenone-lesioned animals, was blocked by chronic VPA treatment. These findings strongly support the therapeutic potential of VPA in Parkinson's disease. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/24613722/Neuroprotection_by_valproic_acid_in_an_intrastriatal_rotenone_model_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(14)00140-7 DB - PRIME DP - Unbound Medicine ER -