The Effect Of Flavopiridol On Neurodegeneration In Niemann-Pick Type C

Dysregulation of cyclin-dependent kinases (cdks) and hyperphosphorylation of the cytoskeletal proteins characterize a subset of human neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick Type C (NPC). It is thought that these cytoskeletal abnormalities eventually lead to development of hallmark cytoskeletal lesions such as neurofibrillary tangles and axonal spheroids. The naturally occurring npc-1 mutant mice mimic human NPC clinically and neuropathologically, in displaying activation of cdk5, mitotic cdc2, and cdk4, with concomitant cytoskeletal pathology and neurodegeneration. We availed of this mouse model and of a specific pharmacological inhibitor of cdk4 activity,flavopiridol, to determine whether cdks are necessary for formation of NPC neuropathology. The inhibitor was infused intracerebroventricularly for a 2-week period, initiated at a pathologically incipient stage. We assessed the neuropathology and subsequent motor impairments in NPC mice by immunohistochemistry, Western-blot, H&E staining and hanger-test. Expectedly, flavopiridol at 80 nmoles/d can reduce the hyperphosphorylation of cytoskeleton and improved the behavior of npc mice significantly.