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The spontaneously hypertensive rat (SHR) is an accepted animal model for the study of human MS that reveals all the features of the syndrome when fed high\u2010fat, high\u2010carbohydrate diets. The intake of high\u2010fat diets in rats has been shown to produce brain neuropathology. In humans, MS increases the risk of cognitive impairment, dementia, and Alzheimer's disease. Genistein (GEN) is a phytoestrogen found in soy that lacks feminizing and carcinogenic effects and was found to have neuroprotective and anti\u2010inflammatory effects in many pathological conditions. Considering that multiple data support that natural phytoestrogens may be therapeutic options for CNS maladies, we aim to elucidate if these properties also apply to a rat model of MS. Thus, GEN effects on neuroinflammation, neurogenesis, and cognition were evaluated in SHR eating a fat\/carbohydrate\u2010enriched diet. To characterize the neuropathology and cognitive dysfunction of MS we fed SHR with a high\u2010fat diet (4520 kcal\/kg) along with a 20% sucrose solution to drink. MS rats displayed a significant increase in body weight, BMI and obesity indexes along with an increased in fasting glucose levels, glucose intolerance, high blood pressure, and high blood triglyceride levels. MS rats were injected with GEN during 2\u2009weeks a dose of 10\u2009mg\/kg. We found that MS rats showed a decreased number of DCX+ neural progenitors in the dentate gyrus and treatment with GEN increased this parameter. Expression of GFAP was increased in the DG and CA1 areas of the hippocampus and treatment decreased astrogliosis in all of them. We measured the expression of IBA1+ microglia in the same regions and classified microglia according to their morphology: we found that MS rats presented an increased proportion of the hypertrophied phenotype and GEN produced a shift in microglial phenotypes toward a ramified type. Furthermore, colocalization of IBA1 with the proinflammatory marker TNF\u03b1 showed increased proportion of proinflammatory microglia in MS and a reduction with GEN treatment. On the other hand, colocalization with the anti\u2010inflammatory marker Arg1 showed that MS has decreased proportion of anti\u2010inflammatory microglia and GEN treatment increased this parameter. Cognitive dysfunction was evaluated in rats with MS using a battery of behavioral tests that assessed hippocampus\u2010dependent spatial and working memory, such as the novel object recognition test (NOR), the novel object location test (NOL), and the free\u2010movement pattern Y\u2010maze (FMP\u2010YMAZE) and the d\u2010YMAZE. In all of them, MS performed poorly and GEN was able to improve cognitive impairments. These results indicate that GEN was able to exert neuroprotective actions increasing neurogenesis and improving cognitive impairments while decreasing astrogliosis, microgliosis, and neuroinflammatory environment in MS rats. Together, these results open an interesting possibility for proposing this phytoestrogen as a neuroprotective therapy for MS.<\/jats:p>","DOI":"10.1111\/jne.13480","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T01:45:17Z","timestamp":1734313517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The phytoestrogen genistein improves hippocampal neurogenesis and cognitive impairment and decreases neuroinflammation in an animal model of metabolic syndrome"],"prefix":"10.1111","volume":"37","author":[{"given":"Santiago","family":"Ronchetti","sequence":"first","affiliation":[{"name":"Laboratory of Neuroendocrine Biochemistry Instituto de Biolog\u00eda y Medicina Experimental  Buenos Aires 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