Mitochondrial dysfunction, oxidative stress, ER stress and mitochondria-ER crosstalk alterations in a chemical rat model of Huntington's disease: Potential benefits of bezafibrate.

Redox homeostasis, mitochondrial functions, and mitochondria-endoplasmic reticulum (ER) communication were evaluated in the striatum of rats after 3-nitropropionic acid (3-NP) administration, a recognized chemical model of Huntington's disease (HD). 3-NP impaired redox homeostasis by increasing malondialdehyde levels at 28 days, decreasing glutathione (GSH) concentrations at 21 and 28 days, and the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and glutathione S-transferase at 7, 21, and 28 days, catalase at 21 days, and glutathione reductase at 21 and 28 days. Impairment of mitochondrial respiration at 7 and 28 days after 3-NP administration was also observed, as well as reduced activities of succinate dehydrogenase (SDH) and respiratory chain complexes. 3-NP also impaired mitochondrial dynamics and the interactions between ER and mitochondria and induced ER-stress by increasing the levels of mitofusin-1, and of DRP1, VDAC1, Grp75 and Grp78. Synaptophysin levels were augmented at 7 days but reduced at 28 days after 3-NP injection. Finally, bezafibrate prevented 3-NP-induced alterations of the activities of SOD, GPx, SDH and respiratory chain complexes, DCFH oxidation and on the levels of GSH, VDAC1 and synaptophysin. Mitochondrial dysfunction and synaptic disruption may contribute to the pathophysiology of HD and bezafibrate may be considered as an adjuvant therapy for this disorder.

Effects of long-term resveratrol treatment in hypothalamic astrocyte cultures from aged rats.

Aging is intrinsically related to metabolic changes and characterized by the accumulation of oxidative and inflammatory damage, as well as alterations in gene expression and activity of several signaling pathways, which in turn impact on homeostatic responses of the body. Hypothalamus is a brain region most related to these responses, and increasing evidence has highlighted a critical role of astrocytes in hypothalamic homeostatic functions, particularly during aging process. The purpose of this study was to investigate the in vitro effects of a chronic treatment with resveratrol (1 µM during 15 days, which was replaced once every 3 days), a recognized anti-inflammatory and antioxidant molecule, in primary hypothalamic astrocyte cultures obtained from aged rats (24 months old). We observed that aging process changes metabolic, oxidative, inflammatory, and senescence parameters, as well as glial markers, while long-term resveratrol treatment prevented these effects. In addition, resveratrol upregulated key signaling pathways associated with cellular homeostasis, including adenosine receptors, nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase 1 (HO-1), sirtuin 1 (SIRT1), proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and phosphoinositide 3-kinase (PI3K). Our data corroborate the glioprotective effect of resveratrol in aged hypothalamic astrocytes, reinforcing the beneficial role of resveratrol in the aging process.