Funded Studies
This grant builds upon the research from a prior grant: rAAV-ribozyme Mediated Parkin Knockdown as a Pre-clinical Model of Parkinson's Disease
Objective/Rationale:
Recently we have demonstrated that NF-kB activation is induced in vivo in the SNpc of Parkinson's disease patients and an MPTP-pre-clinical model, and that selective inhibition of NF-kB by NBD peptide results in significant protection of the nigrostriatum against MPTP toxicity in a pre-clinical model. Now, in order to translate this NF-kB-based therapeutic approach to the clinic, we will test the efficacy of NBD peptide in a more relevant pre-clinical model, the best available model for human PD.
Project Description:
The best available pre-clinical MPTP models of Parkinson's disease will be treated with NBD peptides. First, we will examine if this peptide enters the brain. Second, since activation of glial cells plays an important role in the pathogenesis of PD, we will determine if NBD peptide inhibitis the activation of glial cells in. Third, since dopaminergic neurons in PD patients disappear, we will investigate if NBD peptide protects these neurons in the pre-clinical model. Fourth, we will examine if NBD peptide restores the level of neurotransmitters in the model. Fifth, similar to PD, MPTP models display motor abnormalities. Therefore, we will test if NBD peptide improves locomotor activities in the model.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
In spite of extensive research on the pathogenesis of PD, no effective therapy is available to halt this disorder. Studies proposed from various angles in this grant application will delineate the efficacy of NBD peptides in inhibiting the disease process of PD in a non-human primate model of PD. Therefore, results obtained from this proposal will help shed greater light on the potential to treat PD patients with NBD peptides as primary or adjunct therapy.
Anticipated Outcome:
Recent studies suggest that inflammation plays an important role in nigrostriatal degeneration in PD. Because NF-kB is an important regulator of inflammation and we have shown that it participates in the loss of dopaminergic neurons in MPTP pre-clinical models of PD, we expect selective inhibition of NF-kB by NBD peptide will protect dopaminergic neurons, normalize neurotransmitters and restore locomotor activities in hemiparkinsonian pre-clinical models. In summary, we hope to learn whether an NF-kB-based therapy holds potential to move from the bench to the PD clinic.
Final Outcome
MPTP pre-clinical models share many of the typical biochemical, morphological and behavioral features of PD. Due to the facts that chronic inflammation plays a role in the pathogenesis of PD and that NF-kappaB is an important regulator of inflammation, we investigated the role of NF-kappaB activation in the loss of dopaminergic neurons in an MPTP pre-clinical model. Here we demonstrate that activation of NF-kappaB is induced in vivo in the substantia nigra of an MPTP pre-clinical model and that injection of NBD peptides is capable of inhibiting nigral activation of NF-kappaB and nigral expression of inducible nitric oxide synthase, an NF-kappaB-dependent pro-inflammatory molecule, in the pre-clinical model. Furthermore, we have also found that NBD peptides, when treated from 7 d after intracarotid injection of MPTP, protected dopaminergic neurons in the nigra partially, restored the level of dopamine in the striatum, and improved motor function in an MPTP pre-clinical model. These results suggest that an NF-kappaB-based primary or adjunct treatment using NBD peptides may be useful in PD patients.