Neuroprotective effects of kefir on HFCS-induced hypoxic and autophagic alterations in hippocampal subregions and cerebral cortex

Abstract

High-fructose corn syrup (HFCS) is a widely consumed sweetener associated with adverse effects on brain metabolism, yet its cellular and molecular mechanisms in distinct brain regions remain poorly characterised. We investigated how HFCS exposure affects specific hippocampal subregions and cortical tissue, and whether kefir co-administration could attenuate these effects. Male Wistar rats were assigned to four groups: control, kefir, HFCS, and HFCS+kefir. After eight weeks, we assessed HIF-1α (hypoxia), Beclin-1 (autophagy), neuronal nitric oxide synthase (nNOS), and Lin28 (neurogenesis) in the dentate gyrus (DG), CA1, and CA3 hippocampal subregions and in the cerebral cortex (Ctx) by immunohistochemistry. HFCS produced region-specific molecular disturbances across all brain areas examined. In the DG, Lin28 expression fell significantly while HIF-1α rose, consistent with reduced neurogenic activity alongside a hypoxia-like metabolic state. In CA1, both HIF-1α and Beclin-1 were markedly elevated, with concurrent hypoxic signalling and autophagic dysregulation. Beclin-1 and nNOS were significantly elevated in CA3, and the cerebral cortex showed comparable increases in both markers. Cortical HIF-1α trended upward but did not reach statistical significance. Kefir co-administration significantly attenuated these changes across all regions: HIF-1α was suppressed in DG and CA1, Beclin-1 was reduced in CA1, CA3, and Ctx, nNOS was diminished in CA1, CA3, and Ctx, and Lin28 immunoreactivity in the DG was largely preserved, suggesting a protective effect on neurogenic potential. These data show that HFCS induces region-specific neurobiological disruption across hippocampal subfields and cerebral cortex, and that kefir supplementation can substantially counteract these molecular changes. Kefir’s neuroprotective action likely involves modulation of hypoxic signalling, autophagic balance, and nitrosative stress via metabolic and gut-brain axis pathways.