Quercetin Administration Following Hypoxia-Induced Neonatal Brain Damage Attenuates Later-Life Seizure Susceptibility and Anxiety-Related Behavior: Modulating Inflammatory Response

Abstract

BackgroundNeonatal seizures commonly caused by hypoxia could lead to brain injury and cognitive deficits. Quercetin could cross the blood brain barrier and exerts neuroprotective effects in many neurological disease settings. In this study, we aim to investigate the role of quercetin in attenuating cognitive impairment following hypoxia-induced neonatal seizure (HINS).MethodSprague-Dawley rats at P7 were exposed to a premixed gas in a hypoxic chamber to induce brain injury, and then continuously administered with quercetin for 21 days. Pentylenetetrazol kindling was used to induce seizures in the evolution. After the hypoxic lesion was stablished, anxiety-related behavior of rats after HINS was assessed using open field test. Memory impairment of rats after HINS was evaluated using novel object-recognition test and elevated plus maze test. The serum and hippocampal concentrations of TNF-a, iNOS, IL-6 MCP-1, and IL-1β were measured using ELISA. The mRNA expression levels of TNF-a, iNOS, IL-6 in the hippocampus were determined using qRT-PCR. The protein levels of TLR4, NF-κB p65, and p-NF-κB p65 in the hippocampus were determined using Western blot.ResultsQuercetin administration significantly reduced later-life seizure susceptibility, anxiety-related behavior, and memory impairments in the rats following the HINS when compared to the HINS group without treatment. Both serum and hippocampal proinflammatory cytokines levels were significantly elevated in the rat after HINS. TLR4 protein expressions were increased in the HINS group when compared to control group, and decreased in the group of quercetin. The protein level of p-NF-κB p65 was significantly lower in the quercetin group compared to the HINS group.ConclusionWe demonstrated that Quercetin significantly reduced susceptibility to later-life seizures. Quercetin could downregulate inflammatory response through TLR4/ NF-κB pathway, thereby attenuating HINS-induced anxiety, hippocampal memory impairment, and cognitive impairment in later life following HINS.

The P2X7 receptor contributes to seizures and inflammation‐driven long‐lasting brain hyperexcitability following hypoxia in neonatal mice

“…Previous studies have demonstrated increased levels of microgliosis and cytokine release, particularly IL‐1β, in this hypoxia‐induced neonatal seizure model, with this being associated with neuronal damage and aberrant neuron morphology in the hippocampus in later life (Quinlan et al, 2019). Moreover, targeting inflammation during hypoxia has shown success in reducing neonatal seizure severity and to alleviate adverse long‐term clinical outcomes (Quinlan et al, 2019; Wu et al, 2022).…”

“…Importantly, reducing inflammatory signalling has anticonvulsant effects in multiple seizure models (Leavy & Jimenez Mateos, 2020). More specifically, blocking inflammation with the anti‐inflammatory drugs candesartan and quercetin was effective in protecting from neonatal seizures and the resultant brain hyperexcitability in mice and rats, respectively (Quinlan et al, 2019; Wu et al, 2022).…”

Study on the mechanism of Gastrodiae Rhizoma, Lycii Fructus, and Ziziphi Spinosae Semen in sedation and tranquillising mind

“…Furthermore, lower concentrations of Quercetin were observed to have positive effects on shoaling behavior and anxiety in Zebra sh [17]. Quercetin, known for its mitochondrial protective properties, shows potential in treating anxiety induced by methylamphetamine (MA) [18] and can also mitigate anxiety resulting from hypoxia-induced neonatal seizures (HINS) [19] by down-regulating the in ammatory response through the TLR4/NF kappa B pathway. Atropine, an anticholinergic drug, has the potential to serve as adjunctive therapy for Ketamine sedation [20].…”

Analysis of the action mechanisms and targets of herbal anticonvulsants highlights opportunities for therapeutic engagement with refractory epilepsy

“…Another flavonoid, quercetin, which is enriched in Allium cepa [ 85 , 86 ] and several common fruits and vegetables, has shown potent anti-inflammatory action by inhibiting the TLR4/NF-kB signaling in animal models of epilepsy [ 85 , 86 ]. In the same vein, in KA-injected rats, rutin from Ruta graveolens , attenuated the release of inflammatory molecules like IL-1β, IL-6, TNF-α, and high-mobility group box 1 (HMGB1) protein and suppressed the IL-1R1 and toll-like receptor 4 (TLR4) expression, preventing seizures [ 87 ].…”