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The Journal of Neuroscience, October 28, 2009, 29(43):13543-13556; doi:10.1523/JNEUROSCI.4144-09.2009

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Neurobiology of Disease
Simvastatin Inhibits the Activation of p21^ras and Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease

Anamitra Ghosh,¹ Avik Roy,¹ Joanna Matras,¹ Saurav Brahmachari,¹ Howard E. Gendelman,² and Kalipada Pahan¹

¹Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, and ²Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198

Correspondence should be addressed to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 320, Chicago, IL 60612. Email: kalipada_pahan{at}rush.edu

Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. We investigated whether simvastatin, a Food and Drug Administration-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice. First, MPP⁺ induced the activation of p21^ras and nuclear factor-B (NF-B) in mouse microglial cells. Inhibition of MPP⁺-induced activation of NF-B by p21^ras, a dominant-negative mutant of p21^ras, supported the involvement of p21^ras in MPP⁺-induced microglial activation of NF-B. Interestingly, simvastatin attenuated activation of both p21^ras and NF-B in MPP⁺-stimulated microglial cells. Consistently, we found a very rapid activation of p21^ras in vivo in the substantia nigra pars compacta of MPTP-intoxicated mice. However, after oral administration, simvastatin entered into the nigra, reduced nigral activation of p21^ras, attenuated nigral activation of NF-B, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Similarly, pravastatin, another cholesterol-lowering drug, suppressed microglial inflammatory responses and protected dopaminergic neurons in MPTP-intoxicated mice, but at levels less than simvastatin. Furthermore, both the statins administered 2 d after initiation of the disease were still capable of inhibiting the demise of dopaminergic neurons and concomitant loss of neurotransmitters, suggesting that statins are capable of slowing down the progression of neuronal loss in the MPTP mouse model. Therefore, we conclude that statins may be of therapeutic benefit for PD patients.

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Received Aug. 22, 2009; accepted Sept. 11, 2009.

Correspondence should be addressed to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 320, Chicago, IL 60612. Email: kalipada_pahan{at}rush.edu

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