Pentoxifylline targets TLR4/MyD88/NF-κB signaling to ameliorate neuroinflammation and metabolic dysfunction in a rat model of chronic hypoperfusion-induced vascular cognitive impairment

Tangeretin ameliorates sepsis-induced neurocognitive impairment in adult male mice by suppressing Akt-driven glycolytic reprogramming and neuroinflammation.

BACKGROUND AND PURPOSE Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, frequently leads to long-term cognitive impairment. Tangeretin, a polymethoxylated citrus flavonoid, has neuroactive and anti-inflammatory properties. We investigated whether tangeretin protects against sepsis-associated neurocognitive deficits and delineated the underlying mechanisms, focusing on Akt signalling and microglial metabolism. EXPERIMENTAL APPROACH Sepsis was induced by caecal ligation and puncture in mice. Tangeretin (15 or 30 mg·kg-1·day-1, intraperitoneal) was initiated immediately after surgery and maintained throughout the study. Cognitive function was assessed by Morris water maze and novel object recognition. Hippocampal microglial activation and neuroinflammation were quantified. In vitro, BV2 cells and primary microglia were exposed to lipopolysaccharide (LPS, 1 μg·ml-1) with/without tangeretin (40 μM) to measure cytokine production, migration and Akt activity. Direct tangeretin-Akt interaction was tested by surface plasmon resonance and cellular thermal shift assay. Metabolic readouts focused on glycolysis. KEY RESULTS Tangeretin improved sepsis-induced cognitive deficits, decreased hippocampal microglial activation, and lowered proinflammatory cytokine levels and microglial migration. It exerted anti-inflammatory effects via inhibition of the Akt pathway, and pharmacological Akt activation blocked these effects. Surface plasmon resonance and cellular thermal shift assay showed hat tangeretin binds Akt. Metabolically, tangeretin reduced LPS-induced glycolysis (decreased extracellular acidification rate and glycolytic capacity), consistent with diminished Akt phosphorylation and microglial activation. CONCLUSION AND IMPLICATIONS Tangeretin mitigates sepsis-associated neuroinflammation and cognitive impairment by targeting microglial Akt signalling and restraining glycolytic reprogramming. These data support tangeretin as a mechanistically informed candidate for adjunctive therapy in sepsis-related neurocognitive dysfunction.

Thymosin β4 Mitigates Acute Cerebral Infarction Via Inhibition of the TLR4/NF-κB Pathway and Suppression of Neuronal Pyroptosis.

β-Hydroxybutyrate induces microglial M2 polarization by inhibiting the NF-κB/NLRP3 pathway to ameliorate cerebral ischemia–reperfusion injury

Elevated endogenous BHB under obese conditions exerts neuroprotective effects against CIRI, and exogenous BHB can mimic this effect.

Rosmarinic acid modulates microglial Nrf2/HO-1 and NF-κB-NLRP3 signaling in vascular dementia: Multi-omics and experimental evidence.

BACKGROUND Chronic cerebral hypoperfusion contributes to cognitive decline through interacting vascular, inflammatory, and redox abnormalities. Whether rosmarinic acid (RA) modifies these processes through microglial Nrf2/HO-1 and NF-κB-NLRP3 signaling has not been adequately defined. METHODS RA was evaluated in bilateral common carotid artery stenosis (BCAS) mice and OGD-exposed microglial models using a framework that combined behavioral and imaging assessments, histopathology, transcriptomic profiling, computational prediction, cellular thermal shift assays (CETSA), and genetic or pharmacological pathway intervention. RESULTS RA attenuated cognitive and anxiety-like behavioral abnormalities, neuronal injury, corpus callosum demyelination, brain microstructural alterations, and mitochondrial ultrastructural damage in BCAS mice. Multi-omics analyses identified microglia as a prominent disease-responsive cell population and highlighted oxidative stress, neuroinflammation, and BBB disruption as major pathological processes. Molecular docking and dynamics simulations predicted interactions of RA with Nrf2, P65, and NLRP3, whereas CETSA supported cellular target engagement with Nrf2 and P65. In BV2 cells and primary microglia, RA promoted Nrf2 nuclear translocation and HO-1 expression while reducing ROS accumulation, P65 nuclear translocation, phospho-P65, NLRP3, N-GSDMD, Caspase-1 p20, IL-1β, and IL-18. Nrf2 knockdown and ML385 attenuated these effects. Conditioned-medium experiments further indicated that RA-mediated regulation of microglia reduced neuronal and synaptic injury. In vivo, RA improved redox homeostasis, reduced MMP-2 and MMP-9, and restored ZO-1 and Occludin expression. CONCLUSION RA ameliorated cognitive dysfunction in BCAS mice by suppressing microglial oxidative stress and neuroinflammation and attenuating BBB-related disruption. Collectively, the data suggest that RA provide a pharmacological strategy for BCAS-associated cognitive impairment.

Targeting the Redox–NF-κB/NLRP3 axis with intranasal liposomal minocycline mitigates aluminum-induced cognitive and structural deficits

Cobrotoxin suppresses TLR4-NF-κB/STAT1 signaling to mitigate glia-mediated neuroinflammation and motor deficits in Parkinson's disease.

Chronic neuroinflammation is implicated in the pathogenesis of Parkinson's disease (PD), contributing to progressive dopaminergic neuron loss. Cobrotoxin (CoTX), a short-chain α-neurotoxin isolated from Naja atra venom, exerts anti-inflammatory and analgesic effects in several inflammation-related disease models. However, whether CoTX modulates glia-mediated neuroinflammation or confers neuroprotection in PD remains unknown. In this study, we conducted a randomized, placebo-controlled clinical trial and preclinical animal studies to explore the therapeutic efficacy and mechanisms of CoTX in PD. A 12-day subcutaneous regimen of Cobratide (an injectable form of CoTX), consisting of 70 μg daily for 5 days, a 2-day interval, and another 5-day course, significantly improved motor symptoms in PD patients, as reflected by the UPDRS Part II + III scores, with a well-tolerated safety profile. These beneficial effects were further validated in both MPTP- and lipopolysaccharide-induced PD mouse models. Specifically, intranasal administration of CoTX ameliorated motor coordination defects, attenuated dopaminergic neuronal loss, and suppressed glia-mediated neuroinflammation in the substantia nigra of MPTP-challenged mice. Mechanistically, CoTX did not directly protect neurons; instead, it conferred indirect neuroprotection by inhibiting neuroinflammation via blockade of the NF-κB/STAT1 signaling cascades. Furthermore, CoTX functionally interacted with TLR4, which may act as a putative molecular target of CoTX. Collectively, these findings demonstrate the anti-neuroinflammatory and neuroprotective effects of CoTX in PD, highlighting its potential as a promising therapeutic candidate.