Neuroprotective Strategies Against Brain Disorders Cause

National Institute Of Mental Health

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Abstract

Recent reports indicate that axonal degeneration caused by oxidative stress may lead to brain disorders such as Alzheimer's dementia, Parkinson's disease, stroke, head trauma, neuroAIDS, Hallervorden-Spatz syndrome, and possibly schizophrenia. The mission of our research unit is to develop neuroprotective strategies for slowing progressive neuronal injury and improving patient's quality-of-life. We want to study whether clinical deterioration in degenerative brain disorders could be retarded by gene induction in brain cells through preconditioning procedures. Our research hypothesis is based on prior in vivo results that preconditioning stress can protect brain neurons against ischemia/reperfusion brain injury in animal models. We recently developed a human brain cell model to investigate underlying molecular mechanism of compensatory neuroprotection induced by preconditioning procedures. In this human brain cell model, preconditioning stress for a brief period significantly induced the expression of redox factor-1 (Ref-1), neuronal nitric oxide synthase (NOS1/nNOS), MnSOD, Bcl-2, and thioredoxin without altering the expression of heat shock proteins (e.g., HO-1 and HO-2). Interestingly, the induction of NOS1 promotes neuroprotection since the inhibition of NOS1 prevented the preconditioning-induced neuroprotection. Preconditioning induction of NOS1mRNA and transcription of NOS1 protein activated cGMP and PKG, leading to an increase in the expression of a potent antioxidative protein--thioredoxin (ED50 <200 nM). Moreover, inhibition of mRNA by antisense oligonucleotides blocked not only the expression thioredoxin but also neuroprotection induced by preconditioning stress. Consistently, inhibition of thioredoxin reductase prevented neuroprotection produced by either endogenously induced or exogenously administered thioredoxin. Furthermore, our preliminary results indicate that the induction of thioredoxin can protect human brain cells against oxidative injury caused by MPP+, a parkinsonism producing neurotoxin. Based on these new findings, we propose to investigate the role of cGMP in the induction of cytoprotective genes (e.g., thioredoxin and MnSOD), antiapoptotic genes (e.g., Bcl-2) and other novel genes for compensatory neuroprotection in both cell and animal models. In conclusion, cGMP may mediate preconditioning-induced cellular adaptation for survival primarily acting through the expression of antioxidative and antiapoptotic genes and their proteins.