Impairment of neurovascular coupling in the hippocampus due to decreased nitric oxide bioavailability supports early cognitive dysfunction in type 2 diabetic rats.

Autor: Gonçalves JS; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal., Seiça RM; Faculty of Medicine, University of Coimbra, Coimbra, Portugal., Laranjinha J; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: laranjin@ci.uc.pt., Lourenço CF; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: cflmarques@uc.pt.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2022 Nov 20; Vol. 193 (Pt 2), pp. 669-675. Date of Electronic Publication: 2022 Nov 11.
DOI: 10.1016/j.freeradbiomed.2022.11.009
Abstrakt: Numerous epidemiological and preclinical studies have established a strong correlation between type 2 diabetes (T2DM) and cognitive impairment and T2DM is now established as an undisputable risk factor in different forms of dementia. However, the mechanisms underlying cognitive impairment in T2DM are still not fully understood. The temporal and spatial coupling between neuronal activity and cerebral blood flow (CBF) - neurovascular coupling (NVC) - is essential for normal brain function. Neuronal-derived nitric oxide ( ⦁ NO) produced through the nNOS-NMDAr pathway, is recognized as a key messenger in NVC, especially in the hippocampus. Of note, impaired hippocampal perfusion in T2DM patients has been closely linked to learning and memory dysfunction. In this study, we aimed to investigate the functionality of NVC, in terms of neuronal- • NO signaling and spatial memory performance, in young Goto-Kakizaki (GK) rats, a non-obese model of T2DM. For that, we performed direct and simultaneous measurements of • NO concentration dynamics and microvascular CBF changes in the hippocampus upon glutamatergic activation. We found that limited • NO bioavailability, connected to shorter and faster • NO transients in response to glutamatergic neuronal activation, is associated with decreased hemodynamic responses and a decline in spatial memory performance. This evidence supports a close mechanistic association between neuronal-triggered • NO concentration dynamics in the hippocampus, local microvascular responses, and cognitive performance in young diabetic animals, establishing the functionality of NVC as a critical early factor to consider in the cascade of events leading to cognitive decline in T2DM. These results suggest that strategies capable to overcome the limited • NO bioavailability in early stages of T2DM and maintaining a functional NVC pathway may configure pertinent therapeutic approaches to mitigate the risk for cognitive impairment in T2DM.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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