NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6‐OHDA rat model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder of the basal ganglia, associated with the inappropriate death of dopaminergic neurons of the substantia nigra pars compacta (SNc). Here, we show that adenovirally mediated expression of neuronal apoptosis inhibitor protein (NAIP) ameliorates the loss of nigrostriatal function following intrastriatal 6-OHDA administration by attenuating the death of dopamine neurons and dopaminergic fibres in the striatum. In addition, we also addressed the role of the cysteine protease caspase-3 activity in this adult 6-OHDA model, because a role for caspases has been implicated in the loss of dopamine neurons in PD, and because NAIP is also a reputed inhibitor of caspase-3. Although caspase-3-like proteolysis was induced in the SNc dopamine neurons of juvenile rats lesioned with 6-OHDA and in adult rats following axotomy of the medial forebrain bundle, caspase-3 is not induced in the dopamine neurons of adult 6-OHDA-lesioned animals. Taken together, these results suggest that therapeutic strategies based on NAIP may have potential value for the treatment of PD.

New Approaches and Therapeutics Targeting Apoptosis in Disease

“…Even more important, surviving neurons were still functional, as demonstrated by spatial learning tests (Xu et al, 1997;. Overexpression of neuronal apoptosis inhibitory protein also attenuated death of dopamine neurons and dopaminergic fibers in a model of Parkinson's disease (Crocker et al, 2001). Thus, these studies demonstrate that IAPs are promising targets for intervention in several neurodegenerative diseases.…”

The inhibitors of apoptosis: there is more to life than Bcl2

“…Adenoviral vectors encoding NAIP, c-IAP1, and c-IAP2 have been shown to suppress apoptosis in the sciatic nerve axotomy model (Perrelet et al, 2000(Perrelet et al, , 2002, and adeno-XIAP in an optic nerve axotomy model (Kugler et al, 2000). Additionally, NAIP overexpression has been shown to be protective both histologically and functionally in the 6-hydroxydopamine model of Parkinson's disease (Crocker et al, 2001). Finally, transgenic mice overexpressing XIAP in the brain are protected from the effects of MPTP toxicity (Crocker et al, 2003).…”

Gene therapy progress and prospects: Parkinson's disease

“…These findings have now been extended to other experimental paradigms. The human neuronal apoptosis inhibitor protein (NAIP), delivered to the SN of rats by intrastriatal inoculation of a recombinant type 5 adenovirus (Ad) vector, 1 protected the animals against 6-OHDA toxicity administered 1 week after the vector, as measured by immunohistochemistry and motor phenotype studies up to 28 days later. Prevention of the apoptotic protease-activating factor-1 (apaf-1)-dependent activation of caspase 9, using a recombinant adenoassociated virus (AAV) vector expressing a dominantnegative apaf-1 derivative, 2 protected mice against the effects of intra-peritoneal injections of MPTP administered 2 weeks after vector inoculation.…”