A Cystine-Rich Whey Supplement (Immunocal®) Delays Disease Onset and Prevents Spinal Cord Glutathione Depletion in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Depletion of the endogenous antioxidant, glutathione (GSH), underlies progression of the devastating neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Thus, strategies aimed at elevating GSH may yield new therapeutics for ALS. Here, we investigated the effects of a unique non-denatured whey protein supplement, Immunocal®, in the transgenic Gly position 93 to Ala (G93A) mutant hSOD1 (hSOD1G93A) mouse model of ALS. Immunocal® is rich in the GSH precursor, cystine, and is therefore capable of bolstering GSH content. Transgenic hSOD1G93A mice receiving Immunocal® displayed a significant delay in disease onset compared to untreated hSOD1G93A controls. Additionally, Immunocal® treatment significantly decreased the rate of decline in grip strength and prevented disease-associated reductions in whole blood and spinal cord tissue GSH levels in end-stage hSOD1G93A mice. However, Immunocal® did not extend survival, likely due to its inability to preserve the mitochondrial GSH pool in spinal cord. Combination treatment with Immunocal® and the anti-glutamatergic compound, riluzole, delayed disease onset and extended survival in hSOD1G93A mice. These findings demonstrate that sustaining tissue GSH with Immunocal® only modestly delays disease onset and slows the loss of skeletal muscle strength in hSOD1G93A mice. Moreover, the inability of Immunocal® to rescue mitochondrial GSH in spinal cord provides a possible mechanism for its lack of effect on survival and is a limiting factor in the potential utility of this supplement as a therapeutic for ALS.

Redox Mechanisms in Neurodegeneration: From Disease Outcomes to Therapeutic Opportunities

“…Decreased cysteine levels have been reported in the plasma of G93A mice (25). Supplementation of the diet with a cysteinerich whey isolate rescues GSH content in tissues and delays disease onset in the G93A mice (434). The involvement of redox imbalance in ALS is further supported by studies involving the G93A mice on a gclc deleted background.…”

Mitochondrial Glutathione: Recent Insights and Role in Disease

“…Thus, strategies aimed at elevating GSH may yield new therapeutics for ALS. In this regard, a recent study evaluated the use of a nutritional cystine-rich GSH precursor, whey supplement (Immunocal ( ® )), in the mutant hSOD1 (G93A) mouse model of ALD [ 120 ]. The administration of the GSH precursor significantly delayed the disease onset in the transgenic hSOD1(G93A) mice, but without extending life span, most likely due to the inability to recover the mitochondrial GSH pool in the spinal cord [ 120 ].…”

Cysteine Metabolism in Neuronal Redox Homeostasis

“…As ALS is associated with elevated oxidative stress, depletion of cysteine could play a role in the process. Supplementation of the diet with a cysteine-rich whey isolate rescues glutathione content in tissues and delays disease onset in the G93A mice [73].…”