A Cystine‐Rich Whey Supplement (Immunocal®) Provides Neuroprotection from Diverse Oxidative Stress‐Inducing Agents In Vitro by Preserving Cellular Glutathione

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.

Therapeutic potential of glutathione-enhancers in stress-related psychopathologies

“…Recently, the antioxidant potential of Immunocal ® , a whey protein supplement enriched in cystine-donor proteins has been studied. Cystine, the oxidized form of cysteine, is resistant to proteolysis and can be transported via the blood flow to target organs and tissues, where it is absorbed by cells and reduced to two cysteine molecules (Winter, Ross et al 2017). Rat cerebellar granule neurons treated with a medium containing 3.3 % Immunocal ® for 24 h were protected from the drop in GSH induced by a pro-apoptotic drug termed HA14-1 (Zimmermann, Loucks et al 2007;Winter, Ross et al 2017).…”

The cysteine-rich whey protein supplement, Immunocal®, preserves brain glutathione and improves cognitive, motor, and histopathological indices of traumatic brain injury in a mouse model of controlled cortical impact

“…By preserving brain GSH, Immunocal® could mitigate several of the secondary injury mechanisms that are activated by TBI. In this context, we recently demonstrated that Immunocal® is broadly neuroprotective in vitro and rescues primary cerebellar neurons and various neuronal cell lines from a number of stressors including oxidative damage, nitric oxide, and excitotoxicity (Winter et al, 2017). All of these stressors are believed to contribute to the secondary injury processes post-TBI.…”

“…All of these stressors are believed to contribute to the secondary injury processes post-TBI. Importantly, the neuroprotective effects of Immunocal® observed in cell culture are dependent on the de novo synthesis of GSH (Winter et al, 2017). Thus, it seems probable that at least the neuroprotective actions of Immunocal® observed in this mouse model of TBI are due largely to its capacity to act as a cysteine delivery system and thereby, a precursor pool for GSH synthesis.…”

Control of Reactive Oxygen Species for the Prevention of Parkinson’s Disease: The Possible Application of Flavonoids

“…ROS can damage proteins by oxidation of amino acids, because all amino acids are susceptible to oxidation, especially cysteine and methionine [ 92 , 93 ]. Protein oxidation is initiated by interactions with hydroxyl radicals inducing protein modifications, such as protein-protein cross-linking, amino acid side chain modification, protein fragmentation by oxidation of the protein backbone, and enzyme inactivation resulting in activity loss.…”