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The accumulation of Aβ plaques and hyperphosphorylation of Tau neuropathologically characterize Alzheimer's disease (AD). Synaptic dysfunction and endoplasmic reticulum (ER) stress precede overt neuropathology. ER stress is characterized by the accumulation of unfolded/misfolded proteins, which leads to activation of the adaptive signaling pathway, the unfolded protein response (UPR). Chronic or unresolved ER stress, as in disease, is maladaptive and triggers the integrated stress response (ISR). We hypothesize that targeted attenuation of ISR activation would mitigate the early cognitive deficits and molecular pathology in the triple transgenic (3xTg) mouse model of AD. To test this hypothesis, we used an adeno-associated viral (AAV) vector to overexpress BiP, the key ER chaperone and UPR regulator, in the hippocampi of young 3xTg mice. BiP overexpression reduced phosphorylated PERK (pPERK), a marker of ISR activation, and increased synaptic proteins BDNF, PSD95, and choline acetyltransferase marker (ChAT). Hippocampal-dependent working memory, social memory, long-term spatial memory, and REM theta power were improved without changes in locomotion. BiP overexpression reduced neuroinflammation, as evidenced by a decrease in the astrocyte marker GFAP. Additionally, Aβ and Aβ42 levels were reduced in the hippocampus and cortex. Collectively, these findings indicate that modulation of ER stress via BiP overexpression ameliorates early cognitive and molecular alterations associated with AD. Show less

(ACR)-induced neurotoxicity, focusing on oxidative stress, endoplasmic reticulum (ER) stress, neuroinflammation, and apoptosis mechanisms. Fifty male Sprague-Dawley rats were divided into five groups: Control, ACR, GA50 +ACR, GA100 +ACR, and GA100. GA (50 and µmg/kg) and ACR (50 mg/kg) were administered intraperitoneally for 14 days. ACR exposure significantly decreased antioxidant enzyme activities (SOD, GSH, GPx, CAT) and increased malondialdehyde (MDA) levels, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), neuronal nitric oxide synthase (nNOS), and apoptosis-related gene expression (Bax and caspase-3). Histopathological analysis revealed neuronal degeneration and vascular hyperemia, while BDNF, Nrf2, and HO-1 immunoreactivity decreased in the ACR group. GA treatment, particularly at 100 mg/kg, markedly ameliorated these biochemical, molecular, and histopathological alterations. These findings indicate that GA exerts significant neuroprotective effects against ACR-induced brain injury by modulating oxidative stress, ER stress, inflammatory, and apoptotic pathways. Show less

Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less

Parkinson's disease (PD) is a common neurodegenerative disorder involving multiple pathological processes. Bergapten (BeG) exhibits various pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects, but its mechanism of action in PD remains unclear. This study aimed to investigate the neuroprotective effects and underlying mechanisms of BeG in PD models. An in vitro neuroinflammation model was established using LPS-treated astrocytes. In-vitro studies demonstrated that BeG counteracted LPS-induced astrocyte activation by reducing the expressions of GFAP, inflammatory mediators (IL-6, TNF-α, IL-1β), and A1 polarization markers. It alleviated ERS (as indicated by reduced levels of GRP78, CHOP) and apoptosis (as shown by changes in Bax, caspase-3) while enhancing Bcl-2. Mechanistically, BeG suppressed LCN2 expression and JAK2/STAT3 phosphorylation, with LCN2 overexpression attenuating its protective effects. In MPTP-treated mice, BeG improved motor function, preserved dopaminergic neurons, and reduced astrocyte activation and A1 polarization. It increased neurotrophic factors (BDNF, GDNF) while decreasing inflammation, ER stress and apoptotic markers. The inhibition of the LCN2/JAK2/STAT3 pathway was consistently observed in both models, suggesting its central role in BeG's neuroprotective mechanism. These findings suggest that BeG exerts neuroprotective effects in PD by inhibiting the LCN2/JAK2/STAT3 signaling pathway, thereby effectively inhibiting astrocyte activation-mediated neuroinflammation and ERS. Show less

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver dysfunction, driven by hyperammonemia, oxidative stress, neuroinflammation, apoptosis, and endoplasmic reticulum (ER) stress, which disrupt the hepato-encephalic axis and impair cognition and motor functions. Despite its clinical burden, effective therapies that target this multi-organ pathology remain limited. β-Caryophyllene (BCP), an antioxidant and anti-inflammatory dietary sesquiterpene, has not been evaluated for its ability to modulate liver-brain crosstalk in HE. This study investigated the hepatoprotective and neuroprotective effects of BCP in a rat model of thioacetamide (TAA)-induced HE. Rats received TAA (200 mg/kg, i.p.) for three days, followed by BCP (100-400 mg/kg) for 14 days. A comprehensive evaluation included serum biochemistry, oxidative stress indices, inflammatory cytokines, apoptosis-related proteins, neurotrophic factors (BDNF), astroglial activation marker (GFAP), ER stress regulators (GRP78, IRE1, XBP1, PERK, CHOP, ATF6), histopathology, and behavioral outcomes. TAA caused severe hepatic and cerebral injury with elevated liver enzymes, oxidative and inflammatory mediators, ER stress dysregulation, pro-apoptotic signaling, reduced BDNF and GFAP, and impaired motor and exploratory behaviors. BCP treatment dose-dependently restored biochemical and molecular parameters, suppressed oxidative stress and neuroinflammation, normalized ER stress signaling, promoted anti-apoptotic pathways, preserved BDNF and maintained astroglial status as reflected by GFAP, and improved histoarchitecture. Importantly, moderate to high doses fully restored locomotor and exploratory activity, indicating coordinated protection across the hepato-encephalic axis. Here, for the first time, the BCP concurrently mitigates hepatic and cerebral pathology via oxidative, inflammatory, apoptotic, and ER stress pathways, supporting its translational potential as a dual hepatoprotective and neuroprotective candidate for xenobiotic-induced HE and related liver-brain disorders. Show less