Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

Abstract

The aim of this study was to determine the outcomes of oestrogen and melatonin treatments following long-term ovarian hormone depletion on neuroinflammation and apoptotic processes in dentate gyrus of hippocampi. Forty-six female Wistar rats of 22 months of age were used. Twelve of them remained intact, and the other 34 were ovariectomized at 12 months of age. Ovariectomized animals were divided into three groups and treated for 10 weeks with oestrogens, melatonin or saline. All rats were killed by decapitation at 24 months of age, and dentate gyri were collected. A group of 2 month-old intact female rats was used as young control. The levels of pro-inflammatory cytokines and heat shock protein 70 (HSP 70) were analysed by ELISA. The expressions of TNFα, IL1β, GFAP, nNOS, iNOS, HO-1, NFκB, Bax, Bad, AIF, Bcl2 and SIRT1 genes were detected by real-time (RT)-PCR. Western blots were used to measure the protein expression of NFκB p65, NFκB p50/105, IκBα, IκBβ, p38 MAPK, MAP-2 and synapsin I. We have assessed the ability of 17β-oestradiol and melatonin administration to downregulate markers of neuroinflammation in the dentate gyrus of ovariectomized female rats. Results indicated that 17β-oestradiol and melatonin treatments were able to significantly decrease expression of pro-inflammatory cytokines, iNOS and HO-1 in the hippocampus when compared to non-treated animals. A similar age-and long-term ovarian hormone depletion-related increase in GFAP was also attenuated after both melatonin and oestradiol treatments. In a similar way to oestradiol, melatonin decreased the activation of p38 MAPK and NFκB pathways. The treatments enhanced the levels of synaptic molecules synapsin I and MAP-2 and have been shown to modulate the pro-antiapoptotic ratio favouring the second and to increase SIRT1 expression. These findings support the potential therapeutic role of melatonin and oestradiol as protective antiinflammatory agents for the central nervous system during menopause.

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

“…It is well documented that melatonin possesses anti‐inflammatory properties, based generally on its antioxidant action (for review). Previous studies have established the ability of melatonin to inhibit nuclear factor‐kappa B (NF‐κB) and cyclooxygenase (COX)‐2, to prevent activated microglia‐induced production of proinflammatory cytokines and to reduce Aβ‐induced secretion of interleukins IL1‐β and IL‐6 in transgenic mouse models thereby protecting the brain …”

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…A deficiency of the SIRT1 pathway may contribute to the early agerelated brain damage in these mice; thus, the therapeutic use of SIRT1-enhancing agents may protect against age-related nerve cell dysfunction and brain frailty during aging (Cristòfol et al, 2012). In addition, the expression of SIRT1 gene was significantly upregulated after melatonin replacement therapy in the dentate gyrus of ovariectomized females rats (Kireev et al, 2014).…”

Melatonin and inflammation—Story of a double‐edged blade

“…In the liver of aged, ovariectomized female rats, levels of the proinflammatory cytokines TNFα, IL‐1β and, particularly strongly, IL‐6 were reduced, whereas the anti‐inflammatory IL‐10 was substantially upregulated . In the same animal model, TNFα, IL‐1β, and IL‐6 were downregulated by melatonin in dentate gyrus of the hippocampus . Anti‐inflammatory actions of melatonin have been also studied in microglial cell lines.…”