Neuroprotective Strategies Against Brain Disorders Cause

National Institute Of Mental Health

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Abstract

Thioredoxin (Trx) is a multifunctional anti-oxidative and anti-apoptotic redox protein. We recently demonstrated that Trx can be induced by preconditioning procedures and drugs such as l-deprenyl and 17beta-estradiol. For managing progressive neurodegeneration such as Alzheimer's dementia and Parkinson?s disease we proposed to investigate the novel signaling pathway of NOS1-cGMP-PKG for increasing cytoprotective genes and antiapoptotic genes. Recent clinical trials of hormone replacement therapy indicated that hormone therapy's risks out weighed their benefits. These recent clinical reports are at odds with most of the recent preclinical studies; most of basic studies infer that estrogen and 17beta-estradiol may produce beneficial actions in the brain. Significant side effects of stroke, cancer and blood clots have been previously documented in clinical trials of contraceptive pills containing estrogen and progestin; most young women are willing to take risks over unwanted pregnancies. Menopausal women suffering from severe estrogen withdrawal symptoms may also need to make this kind of difficult decision. We investigated elusive actions of estrogen in the brain, which are likely mediated by nuclear estrogen receptors ERalpha and ERbeta. We employed 17beta-estradiol for investigating whether estrogen protects against neurodegeneration in human cell models. Physiological concentrations of 17beta-estradiol activate nuclear estrogen receptors (ERbeta>ERalpha) and up-regulate cGMP-dependent Trx expression. Moreover, l-deprenyl activates the signaling pathway of NO-cGMP-PKG also confers significant neuroprotection possibly through the induction of the redox protein Trx. Our collaborative integrated research project on neuronal adaptation, gene expression, and redox proteomics supports a new hypothesis that induction of NOS1 gene may result in cyto-and neuro-protection via induction of both antioxidative and anti-apoptotic proteins. Human SH-SY5Y cells were sensitive to oxidative stress-induced apoptosis since they contain relatively low levels of Trx. When these neurotrophic cells were subjected to a non-lethal preconditioning stress (2-hour serum deprivation), their NOS1 and Trx were up-regulated, and the cells became more tolerant of oxidative stress with significant neurite extension, indicating that NO may compensatorily protect cells from free radical-induced apoptosis and result in neurotrophic cells with synaptogensis. In the present study, the contribution of Trx to the preconditioning mechanism by which NO/GSNO exerts its neuroprotective effects (hormesis) was investigated. Our results revealed that in addition to estrogen, l-deprenyl GSNO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1, Trx, and Bcl-2. The induction of survival proteins was down stream to the signaling pathway of phosphorylated MAPK/ERK1/2, and c-Myc. Moreover, elevation of Trx, Trx peroxidase-1 and MnSOD inhibited oxidative stress and free radical generation. Interestingly, exogenously administered Trx also increased the synthesis of Bcl-2 and MnSOD leading to inhibition of lipid peroxidation and apoptotic cell death. Preconditioning-induced hormesis is mediated by the elevation of NOS1, NO, and cGMP, plus the biosynthesis of the redox protein Trx and associated Bcl2, MnSOD and trophic factors. For achieving neuroprotection, multi faceted therapeutics derived from Trx may be more effective than using large doses of a single antioxidant.