Resveratrol-Loaded Glutathione-Coated Collagen Nanoparticles Attenuate Acute Seizures by Inhibiting HMGB1 and TLR-4 in the Hippocampus of Mice

Abstract

Epilepsy is a relatively complicated neurological disorder that results in seizures. The use of resveratrol in treating seizures has been reported in recent studies. However, the low bioavailability of resveratrol and the difficulty of reaching the targeted location in the brain reduce its efficacy considerably. The side effects due to the higher concentration of drugs are another matter of concern. The purpose of the present study is to enhance the antiepileptic potential of resveratrol by delivering it to the brain's targeted location by encapsulating it in glutathione-coated collagen nanoparticles. The collagen nanoparticles increase the bioavailability of resveratrol, while the transport of resveratrol to its target location in the brain is facilitated by glutathione. By encapsulating resveratrol in glutathione-coated collagen nanoparticles, the concentration also substantially decreases. Resveratrol encapsulated in synthesized nanoparticles is referred to as nanoresveratrol. In the present study, nanoresveratrol effectiveness was studied through PTZ-induced seizures (PTZ-IS) and the increasing current electroshock (ICES) test. The efficacy of nanoresveratrol was further established using biochemical analysis, histopathological examinations, ELISA and real-time-PCR tests, and immunohistochemistry examination of the hippocampus of mice. Hence, this study is unique in the sense that it synthesized nanoresveratrol by using glutathione-coated collagen nanoparticles, followed by its application to treating seizures. On the basis of the study results, nanoresveratrol was found to be effective in preventing cognitive impairment in the mice and controlling epilepsy seizures to a greater extent than resveratrol. The proposed nanoformulation also reduces the concentration of resveratrol considerably. The present study results show that even 0.4 mg/kg of nanoresveratrol outperforms 40 mg/kg of resveratrol.

Therapeutic potential of stilbenes in neuropsychiatric and neurological disorders: A comprehensive review of preclinical and clinical evidence

“…Indeed, nanoresveratrol was able to significantly reduce cognitive impairment in male Swiss albino mice (25–30 g) undergoing PTZ administration and it was more effective in controlling seizures than resveratrol (Siddiqui et al, 2021). These results were also confirmed by further experiments in which nanoresveratrol was able to attenuate acute seizures by inhibiting the protein known as high mobility group box 1 (HMGB1) and TLR‐4 in the hippocampus of Swiss albino male mice exposed to PTZ injections (Siddiqui et al, 2022).…”

“…and TLR-4 in the hippocampus of Swiss albino male mice exposed to PTZ injections (Siddiqui et al, 2022).…”

A comprehensive insight into the molecular and cellular mechanisms of action of resveratrol on complications of sepsis a systematic review

“…Also, resveratrol could prohibit the activation of the HMGB1 by acting in several ways (Xu et al, 2014). One of the possible inhibitory mechanisms of resveratrol on HMGB1 is that resveratrol suppresses the TLR4/MD‐2 signaling pathway, which ultimately inhibits the release of the HMGB1 (Jiang et al, 2019; Siddiqui et al, 2022). According to the TLR‐dependent function of HMGB1, inhibiting TLR4 by resveratrol could repress the endogenous effects of HMGB1 (Wang et al, 2020).…”

Nanotherapeutics for Alleviating Anesthesia‐Associated Complications

“…An ideal targeted receptor/transporter for delivering cargoes to the brain parenchyma should possess the following features: 1) high expression on the luminal side of brain vasculature and low expression in other tissues; 2) mediation of transcytosis rather than confining cargoes inside endothelial cells; 3) high turnover from cell membranes; 4) broad substrate recognition and resistance to saturation by endogenous substrates. [ 163 , 173 ] Well‐studied ligands for receptor/transporter‐mediated BBB penetration comprise transferrin, OX26 antibody, THR peptide, and CRT peptide for transferrin receptor, [ 163 , 191 ] choline for choline transporters and ACh for ACh transporter, [ 192 ] glucose for glucose transporters (GLUT1), [ 164 , 193 ] receptor‐associated protein (RAP12), angiopep‐2 or apolipoprotein E (ApoE) for lipoprotein receptor‐related protein‐1 (LRP1), [ 163 , 194 ] ApoB and ApoE for low‐density lipoproteins (LDLRs), glutathione (GSH) for GSH transporters, [ 195 ] and rabies virus glycoprotein (RVG29) for nicotinic ACh receptors, [ 196 ] etc. These ligands present varying BBB‐penetrating efficiency and selectivity when conjugated with different cargoes.…”

“…[ 263 ] These nanodrugs primarily function by inhibiting and restoring neurological damages and functional impairments, [ 263 ] suppressing oxidative stress, inflammation, hyperexcitability and apoptosis. [ 195 , 260 ] Integrating clinical antiepileptic drugs with antioxidative and anti‐inflammatory molecules in nanoplatforms with BBB‐penetrating and on‐demand drug‐releasing capabilities may shed light on the effective treatment of epilepsy.…”