Piracetam improves mitochondrial dysfunction following oxidative stress

Abstract

1 Mitochondrial dysfunction including decrease of mitochondrial membrane potential and reduced ATP production represents a common final pathway of many conditions associated with oxidative stress, for example, hypoxia, hypoglycemia, and aging. 2 Since the cognition-improving effects of the standard nootropic piracetam are usually more pronounced under such pathological conditions and young healthy animals usually benefit little by piracetam, the effect of piracetam on mitochondrial dysfunction following oxidative stress was investigated using PC12 cells and dissociated brain cells of animals treated with piracetam.3 Piracetam treatment at concentrations between 100 and 1000 mM improved mitochondrial membrane potential and ATP production of PC12 cells following oxidative stress induced by sodium nitroprusside (SNP) and serum deprivation. Under conditions of mild serum deprivation, piracetam (500 mM) induced a nearly complete recovery of mitochondrial membrane potential and ATP levels. Piracetam also reduced caspase 9 activity after SNP treatment. 4 Piracetam treatment (100-500 mg kg À1 daily) of mice was also associated with improved mitochondrial function in dissociated brain cells. Significant improvement was mainly seen in aged animals and only less in young animals. Moreover, the same treatment reduced antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and glutathione reductase) in aged mouse brain only, which are elevated as an adaptive response to the increased oxidative stress with aging. 5 In conclusion, therapeutically relevant in vitro and in vivo concentrations of piracetam are able to improve mitochondrial dysfunction associated with oxidative stress and/or aging. Mitochondrial stabilization and protection might be an important mechanism to explain many of piracetam's beneficial effects in elderly patients.

Mitochondrial Dysfunction: Common Final Pathway in Brain Aging and Alzheimer’s Disease—Therapeutic Aspects

“…In line with these data are our previous observations of significant mitochondrial protection and enhanced ATP synthesis by piracetam against experimentally induced oxidative as well as nitrosative stress in vitro and after ex vivo treatment, where again aged animals with well-characterized mitochondrial dysfunction benefited most [116]. In agreement with the assumption of mitochondrial membranes as primary target, the beneficial effect of piracetam was similar after experimental impairment of each of the five respiratory chain complexes [116].…”

“…A drug which has been extensively characterized in this respect is the metabolic enhancer piracetam [115], which shows no antioxidant properties but exhibits pronounced mitochondrial protection ex vivo as well as in vitro [116][117][118] Evidences that piracetam might improve disturbed mitochondrial function originate from observations that piracetam improves glucose uptake and utilization as well as ATP production [119][120][121][122]. In line with these data are our previous observations of significant mitochondrial protection and enhanced ATP synthesis by piracetam against experimentally induced oxidative as well as nitrosative stress in vitro and after ex vivo treatment, where again aged animals with well-characterized mitochondrial dysfunction benefited most [116]. In agreement with the assumption of mitochondrial membranes as primary target, the beneficial effect of piracetam was similar after experimental impairment of each of the five respiratory chain complexes [116].…”

Inhibitive Effects of Low Oxygen and Glucose Deprivation on Brain-Pancreas Relative Protein Expression via Hypoxia- Inducible Factor-1 Pathways

“…In our opinion, different from cells such as human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells and proteins like VEGF, in PC12 cells there is a common mechanism for hypoxia and hypoglycemia to regulate the expression of BPRP. Both of hypoxia and hypoglycemia are oxidative stress and lead to mitochondrial dysfunction [40] and then result in HIF-1 signal pathway activation [41]. For example, ROS is accumulated in our study during LOGD [6] and under hypoglycemia [42] in PC12 cells.…”

Amyotrophic Lateral Sclerosis-linked Mutant SOD1 Sequesters Hu Antigen R (HuR) and TIA-1-related Protein (TIAR)

“…In this assay, ATP present in cells drives production of oxyluciferin and light by exogenously added luciferase. This assay reflects cell proliferation and viability, but can also be a measure of mitochondrial function (21,22). Equal numbers of cells from wild-type, G93A, and G37R clones were induced with Dox at different concentrations for 48 h. Luminescence values for mutant clones were expressed as a percent of the wild-type clone.…”