Biology subjects

Tambo, W.

Publications and source records attributed to Tambo, W..

4 recordsLinked to original sources

bioRxiv2025

Vasoactive Neuropeptide Dysregulation: A Novel Mechanism of Microvascular Dysfunction in Vascular Cognitive Impairment

INTRODUCTIONNeuropeptide dysregulation and microvascular injury are involved in pathogenesis of vascular cognitive impairment (VCI); however, the underlying etiology of this pathological axis remains unclear. METHODSWe investigated pathological mediators across varying severities of VCI in a rat model of chronic cerebral hypoperfusion (CCH). Proteomic analysis guided the evaluation of neuropeptide and non-neuropeptide markers associated with vascular and nonvascular dysfunction, which were correlated with cognitive function to determine their role in VCI. RESULTSProteomic analysis revealed vasomotor dysfunction as the primary pathological pathway in VCI. Microvascular vasoconstriction was the earliest and most persistent event, initiating a cascade of both microvascular and nonvascular dysfunction. Dysregulation of vasoactive neuropeptides was identified as the key driver of this process. CGRP supplementation effectively prevented vasoconstriction, and improving cognitive function in CCH. DISCUSSIONThis study suggests dysregulation of vasoactive neuropeptides plays a central role in CCH pathomechanism, with microvascular vasoconstriction acting as the primary mediator. HIGHLIGHTSO_LINeuropeptides are the primary drivers of dominant pathomechanisms underlying CCH. C_LIO_LIEarly vasoactive neuropeptides dysregulation is a key driver of cognitive decline. C_LIO_LIMicrovascular dysfunction precedes classical non-vascular pathologies in CCH. C_LIO_LICapillary constriction precedes and drives amyloid accumulation in CCH. C_LIO_LICGRP mitigates microvascular constriction, enhancing cognitive function in VCI. C_LI Research in ContextO_LISystematic review: The authors reviewed literature from PubMed and Google Scholar, as well as meeting abstracts and presentations. Neuropeptide dysregulation and microvascular injury are increasingly recognized for involvement in the pathogenesis of VCID; however, the underlying etiology of this pathological axis remains unclear. C_LIO_LIInterpretation: Our evidence shows that early, progressive vasoactive neuropeptide dysregulation drives microvascular constriction, constituting a pivotal mechanism in microvascular dysfunction and subsequent cognitive deterioration in chronic cerebral hypoperfusion. The data further elucidate the significant therapeutic efficacy of pharmacological and non-pharmacological interventions directed at vasoactive neuropeptide pathways, which resulted in marked enhancement of cognitive function. C_LIO_LIFuture directions: Our results indicate that aberrant vasoactive neuropeptide regulation constitutes a fundamental pathophysiological mechanism underlying the development and clinical manifestation of VCID. These findings have potentially substantial implications for the development of novel therapeutic strategies targeting this disorder, which represents the second most common etiology of cognitive deterioration. C_LI

neuroscience↗

bioRxiv2025

Endogenous CGRP activates NRF2 signaling via non-electrophilic mechanisms

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is crucial for regulating cellular responses to oxidative stress, making it a significant target for therapeutic interventions. While exogenous NRF2 activators offer significant therapeutic potential, their predominantly electrophilic nature poses considerable challenges for clinical use; the heightened electrophilic reactivity required to achieve therapeutic efficacy raises potential safety concerns. Calcitonin gene-related peptide (CGRP) has shown protective effects against oxidative stress and is involved in NRF2 activation; however, the underlying mechanisms are not fully understood. This study explores the mechanisms underlying endogenous CGRP-mediated NRF2 upregulation by inducing acute or chronic CGRP release through diving reflex (DR) in male Sprague-Dawley rats. Brain tissue proteomics confirmed the upregulation of NRF2-dependent antioxidant transcripts-- predominantly glutathione-related genes--without concurrent elevation of oxidative stress markers in both acute and chronic CGRP exposure paradigms. CGRP potently activated NRF2 in brain and peripheral tissues, evidenced by elevated nuclear and phosphorylated NRF2, increased nuclear:cytosolic NRF2 ratios, and enhanced antioxidant gene transcription--effects substantially attenuated by CGRP antagonism. Reduced glutathione levels increased without concurrent elevations in lipid peroxidation, protein oxidation, or evidence of tissue damage, suggesting CGRP avoids side effects characteristic of electrophilic NRF2 activators. Furthermore, our findings suggest that CGRP-mediated NRF2 activation primarily occurs via non-electrophilic mechanisms, with the p62-KEAP1-NRF2 pathway predominantly active in peripheral organs (lung and kidney), and the AMPK-NRF2 pathway more pronounced in the brain, highlighting the organ-specific nature of the response. Time-dependent variations in CGRP-mediated NRF2 activation were also observed, influencing both the response to CGRP and its impact on oxidative stress resistance. These results suggest that targeting NRF2 with endogenous CGRP may offer a promising therapeutic approach for managing oxidative stress-related diseases, both acute and chronic, across multiple organs, by avoiding electrophilic stress. HighlightsO_LIEndogenous CGRP triggers a potent and non-electrophilic activation of NRF2 signaling. C_LIO_LICGRP increases reduced glutathione levels following both acute and chronic exposures, in contrast to the effects of exogenous electrophilic NRF2 activators. C_LIO_LIIn peripheral organs, CGRP predominantly activates the KEAP1-dependent p62-KEAP1-NRF2 pathway. C_LIO_LIIn the brain, CGRP primarily activates the KEAP1-independent AMPK-NRF2 pathway. C_LIO_LICGRP exhibits time-dependent patterns, where acute exposure leads to a more significant upregulation of NRF2-targeted antioxidative gene expression and chronic exposure confers increased resistance to oxidative stress. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/650677v1_ufig8.gif" ALT="Figure 8"> View larger version (44K): org.highwire.dtl.DTLVardef@ae52a3org.highwire.dtl.DTLVardef@b35d1eorg.highwire.dtl.DTLVardef@1a68f31org.highwire.dtl.DTLVardef@31234_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Intrinsic diving reflex enhances cognitive performance by alleviating microvascular dysfunction in vascular cognitive impairment

Vascular cognitive impairment (VCI) stands as the second-most prominent contributor to cognitive decline, lacking efficacious interventions. Chronic cerebral hypoperfusion (CCH) triggers microvascular dysfunction, which plays a critical role in VCI pathophysiology, emerging as a pivotal therapeutic target. While interventions addressing facets of microvascular dysfunction like angiogenesis and blood-brain barrier functionality show promise, the evaluation of microvascular constriction, another key component, remains unexplored. The diving reflex (DR) represents an oxygen-conserving response, characterized by robust vasodilation and potentially also inducing angiogenesis. In this investigation, we studied DRs functionality and underlying mechanisms within a rat bilateral common carotid artery occlusion induced CCH model. Remarkably, progressive hippocampal microvascular constriction exhibited strong correlations with short-term memory impairment during both early (R2=0.641) and late phases (R2=0.721) of CCH. Implementation of DR led to a significant reduction in microvascular constriction within the hippocampus ([~]2.8-fold) and striatum ([~]1.5-fold), accompanied by enhanced vasodilatory capacity and heightened expression of vasoactive neuropeptides. Furthermore, DR attenuated microvascular degeneration across various brain subregions affected by CCH, concomitant with increased levels of multiple angiogenic factors. The reinforced microvascular integrity facilitated by DR corresponded with significantly improved short-term recognition memory and long-term spatial memory functions observed during the late phase of CCH. The comprehensive and synergistic effects of DR on various aspects of microvascular function and cognitive preservation highlight its potential as a disease-modifying therapeutic strategy in VCI.

neuroscience↗

bioRxiv2024

Intrinsic diving reflex induces potent antioxidative response by activation of NRF2 signaling

AimsThis study aims to elucidate the underlying mechanisms of diving reflex, a powerful endogenous mechanism supporting underwater mammalian survival. Antioxidative responses, observed in marine mammals, may be contributing factors. Using a multi-organ approach, this study assesses whether acute and chronic diving reflex activate nuclear factor-erythroid-2-related factor 2 (NRF2) signaling pathways, which regulate cellular antioxidant responses. MethodsMale Sprague-Dawley rats (n=38) underwent either a single diving session to elicit acute diving reflex, or daily diving sessions for 4-weeks to produce chronic diving reflex. NRF2 (total, nuclear, phosphorylated), NRF2-downstream genes, and malondialdehyde were assessed via Western blot, immunofluorescence, RT-PCR, and ELISA in brain, lung, kidney, and serum. ResultsDiving reflex increased nuclear NRF2, phosphorylated NRF2, and antioxidative gene expression, in an organ-specific and exposure time-specific manner. Comparing organs, the brain had the highest increase of phosphorylated NRF2 expression, while kidney had the highest degree of nuclear NRF2 expression. Comparing acute and chronic sessions, phosphorylated NRF2 increased the most with chronic diving reflex, but acute diving reflex had the highest antioxidative gene expression. Notably, calcitonin gene-related peptide appears to mediate diving reflex effects on NRF2 activation. ConclusionsAcute and chronic diving reflex activate potent NRF2 signaling in the brain and peripheral organs. Interestingly, acute diving reflex induces higher expression of downstream antioxidative genes compared to chronic diving reflex. This result contradicts previous assumptions requiring chronic exposure to diving for induction of antioxidative effects and implies that the diving reflex has a strong translational potential during preconditioning and postconditioning therapies. Key PointsO_LIDiving reflex activates potent NRF2 signaling via multiple mechanisms, including phosphorylation, nuclear translocation, and KEAP1 downregulation with both acute and chronic exposure. C_LIO_LIDiving reflex activates NRF2 via differential pathways in the brain and other organs; phosphorylated NRF2 increases more in the brain, while nuclear NRF2 increases more in the peripheral organs. C_LIO_LIAcute diving reflex exposure induces a more pronounced antioxidative effect than chronic diving reflex exposure, indicating that the antioxidative response activated by diving reflex is not dependent upon chronic adaptive responses and supports diving reflex as both a preconditioning and postconditioning treatment. C_LI

physiology↗