Parkinson's disease (PD) is the second most common neurodegenerative disorder. Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. The present study evaluates the ability of peptide corresponding to the NF-B essential modifier-binding domain (NBD) of I B kinase ␣ (IKK␣) or IKK␤ to prevent nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and establish a role for NF-B in human parkinsonism. First, we found that NF-B was activated within the substantia nigra pars compacta of PD patients and MPTP-intoxicated mice. However, i.p. injection of wild-type NBD peptide reduced nigral activation of NF-B, suppressed nigral microglial activation, protected both the nigrostriatal axis and neurotransmitters, and improved motor functions in MPTP-intoxicated mice. These findings were specific because mutated NBD peptide had no effect. We conclude that selective inhibition of NF-B activation by NBD peptide may be of therapeutic benefit for PD patients.MPTP ͉ NBD peptides ͉ neurodegeneration

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 ( 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.

Peroxisome proliferator-activated receptor (PPAR) α is a transcription factor that regulates genes involved in fatty acid catabolism. Here we provide evidence that PPARα is constitutively expressed in nuclei of hippocampal neurons and surprisingly controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of CREB. Accordingly, Ppara-null, but not Pparb-null, mice are deficient in CREB and memory-associated genes, and have decreased spatial learning and memory. While shRNA knockdown of PPARα in the hippocampus suppressed CREB and NR2A rendering wild type animals markedly poor in consolidating spatial memory, introduction of PPARα to the hippocampus of Ppara-null mice increased hippocampal CREB and NR2A and improved spatial learning and memory. These results together with detailed analyses of CREB, NR2A and spatial learning and memory in bone marrow chimeric animals lacking PPARα in the CNS describe a novel mechanism for transcriptional control of Creb and associated plasticity genes by PPARα.

Increased expression of CD11b, the ␤-integrin marker of microglia, represents microglial activation during neurodegenerative inflammation. However, the molecular mechanism behind increased microglial CD11b expression is poorly understood. The present study was undertaken to explore the role of nitric oxide (

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