Neuroprotective Strategies Against Brain Disorders Cause

National Institute Of Mental Health

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Abstract

It has been suggested that degenerative brain disease such as Alzheimer's dementia, Parkinson's disease, stroke, head trauma, neuroAIDS, Hallervorden-Spatz syndrome, and possibly negative subtype of schizophrenia may be due to oxidative injury caused by toxic free radicals in the brain. Our research mission is to develop neuroprotective strategies for slowing progressive neurodegeneration, to restore cognition and motor functioning, and to improving patient's quality-of-life. With recent advancements in cell and molecular biology it is now feasible to employ gene therapy as a potential treatment of brain disorders. Currently, gene therapy and multipotential stem cells have been targeted for the repair of brain injury in Parkinson's disease and Alzheimer's dementia. However, this procedures reguire tricky brain surgery and dangerous intracerabral infusion procedure. We are investigating whether gene induction evoked by hormesis and preconditioning stress as an aterative procedure in gene therapy for providing neuronal adaptation or compensatory neuroprotection through the induction of cytoprotective genes and new proteins. For this purpose, we recently developed a human brain cell model for investigating hormesis- and/or preconditioning-induced molecular mechanism including gene induction, protein expression, and associated brain functions. Preconditioning stress increases the expression of neuronal nitric oxide synthase (NOS1) leading to cGMP/PKG-dependent induction of a redox protein thioredoxin and a mitochondrial antioxidative protein MnSOD without altering the expression of heat shock proteins (e.g., HO-1 and HO-2) in the human brain-derived SH-SY5Y cells. Moreover, hormesis-induced neuroprotection can be blocked by the inhibition of thioredoxin mRNA by antisense oligonucleotides and also by the inhibition of selenium containing thiredoxin reductase/peroxidase by selective enzyme inhibitors. Finally, both endogenously induced and exogenously administered thioredoxin protect human brain cells against oxidative injury caused by a parkinsonism producing neurotoxin--MPP+. This cGMP/PKG mediated thioredoxin gene induction and neuroprotection is likely becoming the mechanism in common following the treatment of brain cells with analogues of estrogen and statin, all of which increase nitric oxide-mediated events through the activation of NOS expression. With untoward complications of intracerebral injection of viral vector in gene therapy in mind, gene induction using the proposed pharmacogenetic and preconditioning procedures may be more practical than the invasive gene therapy as a non-evasive treatment for managing progressive neurodegeneration in brain disorders.