Triptolide protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats: Implication for immunosuppressive therapy in Parkinson’s disease

• Published in: Neuroscience bulletin 2008-06, Vol.24 (3), p.133-142
• Main Authors: Gao, Jun-Peng, Sun, Shan, Li, Wen-Wei, Chen, Yi-Ping, Cai, Ding-Fang
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenylpyridinium - antagonists & inhibitors; 1-Methyl-4-phenylpyridinium - toxicity; Anatomy; Anesthesiology; Animals; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; CD11b Antigen - analysis; CD11b Antigen - metabolism; Cell Count; Cell Survival - drug effects; Cell Survival - physiology; Disability Evaluation; Diterpenes - pharmacology; Diterpenes - therapeutic use; Dopamine - metabolism; Encephalitis - drug therapy; Encephalitis - immunology; Encephalitis - prevention & control; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Gliosis - drug therapy; Gliosis - immunology; Gliosis - prevention & control; Herbicides - antagonists & inhibitors; Herbicides - toxicity; Human Physiology; Immunosuppression - methods; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Male; Microglia - drug effects; Microglia - immunology; Neurology; Neurons - drug effects; Neurons - immunology; Neurons - pathology; Neurosciences; Original; Original Article; Pain Medicine; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - immunology; Parkinsonian Disorders - physiopathology; Phenanthrenes - pharmacology; Phenanthrenes - therapeutic use; Rats; Rats, Sprague-Dawley; Substantia Nigra - drug effects; Substantia Nigra - immunology; Substantia Nigra - physiopathology; Treatment Outcome; Tyrosine 3-Monooxygenase - analysis; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 1673-7067; 1995-8218
• DOI: 10.1007/s12264-008-1225-9

Objective Neuroinflammation with microglial activation has been implicated to have a strong association with the progressive dopaminergic neuronal loss in Parkinson’s disease (PD). The present study was undertaken to evaluate the activation profile of microglia in 1-methyl-4-phenyl pyridinium (MPP + )-induced hemiparkinsonian rats. Triptolide, a potent immunosuppressant and microglia inhibitor, was then examined for its efficacy in protecting dopaminergic neurons from injury and ameliorating behavioral disabilities induced by MPP + . Methods The rat model of PD was established by intranigral microinjection of MPP+. At baseline and on day 1, 3, 7, 14, 21 following MPP + injection, the degree of microglial activation was examined by detecting the immunodensity of OX-42 (microglia marker) in the substantia nigra (SN). The number of viable dopaminergic neurons was determined by measuring tyrosine hydroxylase (TH) positive neurons in the SN. Behavioral performances were evaluated by counting the number of rotations induced by apomorphine, calculating scores of forelimb akinesia and vibrissae-elicited forelimb placing asymmetry. Results Intranigral injection of MPP + resulted in robust activation of microglia, progressive depletion of dopaminergic neurons, and ongoing aggravation of behavioral disabilities in rats. Triptolide significantly inhibited microglial activation, partially prevented dopaminergic cells from death and improved behavioral performances. Conclusion These data demonstrated for the first time a neuroprotective effect of triptolide on dopaminergic neurons in MPP + -induced hemiparkinsonian rats. The protective effect of triptolide may, at least partially, be related to the inhibition of MPP + -induced microglial activation. Our results lend strong support to the use of immunosuppressive agents in the management of PD.