Possible Signaling by Glutathione and Its Novel Analogue through Potent Stimulation of Frontocortical G Proteins in Normal Aging and in Alzheimer's Disease

Abstract

In the frontal cortex (FC) of the normally aging human brain, glutathione (GSH) and its novel analogue, UPF1, stimulate G proteins more than in Alzheimer's disease (AD) FC. In normal aging and in AD, UPF1 is a more efficient stimulator of G proteins than GSH. In normal FC, both GSH and UPF1 stimulate G proteins, which mediate inhibitory signals to the cAMP system; while in AD, only UPF1 exhibits the same action. Stimulation of G proteins and coupled signaling by GSH antioxidant analogues, as potential signaling molecules, may ameliorate the oxidative impairments of neuronal signaling in AD.

Antioxidant UPF1 attenuates myocardial stunning in isolated rat hearts

“…In our previous studies we have shown that UPF1 modulates the activity of the G-proteins in the brain tissue [12] and can act as a scavenger [6] or a signal molecule increasing the level of glutathione itself or the glutathione redox ratio (our unpublished data).…”

Chromatographic and mass spectrometric analysis of glutathione in biological samples

“…Oxidative stress causes profound alterations of various biological structures including cellular membranes, lipids, proteins and nucleic acids. Oxidative stress is considered to be involved in aging [44][45][46][47][48][49][50][51] and in various diseases such as diabetes mellitus [52][53][54], atherosclerosis [55,56], rheumatoid arthritis [57][58][59][60], Alzheimer's disease [61][62][63], Parkinson's disease [64][65][66] and cancer [67][68][69][70][71]. There is an increasingly growing interest in identifying biomarkers for diseases in which oxidative stress is involved [72].…”

Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo

“…Nevertheless, the effects of GSH to motor neuron degeneration in ALS remains largely unknown, even though abnormalities in GSH are associated with pathophysiological mechanisms underlying neuronal loses in both Parkinson's disease and Alzheimer's disease (Paik et al, 2003;Jha et al, 2000;Karelson et al, 2002;Cecchi et al, 1999). To this end, we measured the GSH and GSSG levels in the spinal cord lumbar region of G93A-SOD1 transgenic mice at three defined stages, namely, disease free, disease onset and disease progression.…”

“…On the other hand, because BSO does not completely deplete mitochondrial and nuclear GSH, other agents, including ethacrynic acid (EA) have been used to effectively deplete cellular, mitochondrial and nuclear GSH (Keelan et al, 2001;Rizzardini et al, 2003). Alterations in GSH synthesis, or in GSH pools, have been associated with neuronal cell death and mimic a variety of human neurodegenerative diseases, such as Parkinson's disease (Bharath et al, 2002;Jha et al, 2000;Mytilineou et al, 2002;Paik et al, 2003), Alzheimer's disease (Adams, Jr. et al, 1991;Cecchi et al, 1999;Janaky et al, 1999;Karelson et al, 2002) and Schizophrenia (Do et al, 2000). Nevertheless, the role of GSH in the pathogenesis of motor neuron degeneration in ALS remained largely undefined.…”