Abstract
Aging is a complex phenomenon associated with oxidative stress and mitochondrial dysfunction. The objective of this study was to investigate the potential ameliorative effects of the phosphodiesterase inhibitor pentoxifylline (PTX) on the aging process and its underlying mechanisms. We treated D-galactose- (D-gal-) induced aging mice with PTX and measured the changes in behavior, degree of oxidative damage, and mitochondrial ultrastructure and content as well as the expression of nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated antioxidant genes and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha- (PGC-1α-) dependent mitochondrial biogenesis genes. The results demonstrated that PTX improved cognitive deficits, reduced oxidative damage, ameliorated abnormal mitochondrial ultrastructure, increased mitochondrial content and Nrf2 activation, and upregulated antioxidant and mitochondrial biogenesis gene expression in the hippocampus of wild-type aging mice. However, the above antiaging effects of PTX were obviously decreased in the brains of Nrf2-deficient D-gal-induced aging mice. Moreover, in hydrogen peroxide-treated SH-SY5Y cells, we found that cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and Nrf2/PGC-1α act in a linear way by CREB siRNA transfection. Thus, PTX administration improved the aging-related decline in brain function by enhancing antioxidative capability and promoting mitochondrial biogenesis, which might depend on increasing Nrf2 and PGC-1α by activating the cAMP-CREB pathway.
Highlights
Aging is a major factor underlying a gradual decline in brain function and has been characterized by pathological features such as reactive oxygen species- (ROS-) induced oxidative stress and mitochondrial dysfunction [1,2,3,4]
It was reported that PTX has ameliorative effects on aging or other pathological processes, such as improving behavioral deficits and anti-inflammatory activity, restoring dopaminergic neurochemical levels and antioxidant activity, and ameliorating mitochondrial function [22,23,24,25]. These findings are supported by our earlier research on the antiaging effects of PTX in aged rats, in which we found that the beneficial function might be related to Nuclear factor-erythroid 2-related factor 2 (Nrf2) activation [22]
We found that PTX administration improved cognitive deficits, enhanced antioxidative capability, and promoted mitochondrial biogenesis in D-gal-induced aging mice, which might be closely related to the upregulation of Nrf2 and PGC-1α through the cyclic adenosine monophosphate (cAMP)-cAMPcAMP response element-binding protein (CREB) pathway
Summary
Aging is a major factor underlying a gradual decline in brain function and has been characterized by pathological features such as reactive oxygen species- (ROS-) induced oxidative stress and mitochondrial dysfunction [1,2,3,4]. The endogenous antioxidant capacity gradually decreases with aging, which leads to massive accumulations of oxidative damage to proteins, nucleic acids, and lipids [5]. Oxidative stress may induce oxidative damage to mitochondria, which need to promote mitochondrial biogenesis to maintain normal mitochondrial function. Previous studies have revealed that a decrease in mitochondrial biogenesis during aging reduces the turnover of mitochondrial components, which further weakens and impairs mitochondrial function and antioxidant defense systems [6,7,8].
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