Abstract
Oxidative stress is a principal mechanism underlying the pathophysiology of neurodegeneration. Therefore, nutritional enhancement of endogenous antioxidant defenses may represent a viable treatment option. We investigated the neuroprotective properties of a unique whey protein supplement (Immunocal®) that provides an essential precursor (cystine) for synthesis of the endogenous antioxidant, glutathione (GSH). Primary cultures of rat cerebellar granule neurons (CGNs), NSC34 motor neuronal cells, or HT22 hippocampal cells were preincubated in medium containing Immunocal and then subsequently treated with agents known to induce oxidative stress. Immunocal protected CGNs against neurotoxicity induced by the Bcl-2 inhibitor, HA14-1, the nitric oxide donor, sodium nitroprusside, CuCl2, and AlCl3. Immunocal also significantly reduced NSC34 cell death due to either H2O2 or glutamate and mitigated toxicity in HT22 cells overexpressing β-amyloid1-42. The neuroprotective effects of Immunocal were blocked by inhibition of γ-glutamyl-cysteine ligase, demonstrating dependence on de novo GSH synthesis. These findings indicate that sustaining GSH with Immunocal significantly protects neurons against diverse inducers of oxidative stress. Thus, Immunocal is a nutritional supplement worthy of testing in preclinical animal models of neurodegeneration and in future clinical trials of patients afflicted by these diseases.
Highlights
Oxidative stress and mitochondrial dysfunction are major factors underlying the pathophysiology of several neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) [1,2,3,4]
A 3.3% solution of Immunocal in culture medium contains 85.3 mM cystine and 30 mM glutamylcysteine, both of which have the potential to act as group of neurodegenerative diseases.Glutathione (GSH) precursors; it should be noted that since both precursors are contained within much larger proteins it is unlikely that all cystine and glutamylcysteine molecules are freely available to be utilized in GSH synthesis
Immunocal was initially studied for application to clinical disorders of immune system deficiency and cancer as an approach to augment the available GSH pool and increase cellular antioxidant and immune system defenses
Summary
Oxidative stress and mitochondrial dysfunction are major factors underlying the pathophysiology of several neurodegenerative disorders including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) [1,2,3,4]. GSH depletion in vitro has been shown to sensitize neurons to oxidative stress and mitochondrial dysfunction, leading to subsequent increases in ROS and apoptotic cell death This was clearly demonstrated by a study in which primary cortical neurons treated with subtoxic levels of the GSH-depleting agent, buthionine sulfoximine (BSO), underwent apoptosis in the presence of trace amounts of extracellular copper [17]. TAR DNA-binding protein-43 (TDP-43) forms cytoplasmic inclusions, which are a hallmark pathology observed in sporadic ALS patients, in cultured neurons subjected to GSH depletion [18]. These studies demonstrate a critical role for GSH depletion in disease progression and pathology in multiple neurodegenerative disease states
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