IκB kinase inhibition remodeled connexins, pannexin-1, and excitatory amino-acid transporters expressions to promote neuroprotection of galantamine and morphine.

Inflammatory pathway and disruption in glutamate homeostasis join at the level of the glia, resulting in various neurological disorders. In vitro studies have provided evidence that membrane proteins connexions (Cxs) are involved in glutamate release, meanwhile, excitatory amino-acid transporters (EAATs) are crucial for glutamate reuptake (clearance). Moreover, pannexin-1 (Panx-1) activation is more detrimental to neurons. Their expression patterns during inflammation and the impacts of IκB kinase (IKK) inhibition, morphine, and galantamine on the inflammatory-associated glutamate imbalance remain elusive. To investigate this, rats were injected with saline or lipopolysaccharide. Thereafter, vehicles, morphine, galantamine, and BAY-117082 were administered in different groups of animals. Subsequently, electroencephalography, enzyme-linked immunosorbent assay, western blot, and histopathological examinations were carried out and various indicators of inflammation and glutamate level were determined. Parallel analysis of Cxs, Panx-1, and EAAts in the brain was performed. Our findings strengthen the concept that unregulated expressions of Cxs, Panx-1, and EAATs contribute to glutamate accumulation and neuronal cell loss. Nuclear factor-kB (NF-κB) pathway can significantly contribute to glutamate homeostasis via modulating Cxs, Panx-1, and EAATs expressions. BAY-117082, via inhibition of IkK, promoted the anti-inflammatory effects of morphine as well as galantamine. We concluded that NF-κB is an important component of reshaping the expressions of Cxs, panx-1, and EAATs and the development of glutamate-induced neuronal degeneration.

Protective effect of tolvaptan against cyclophosphamide-induced nephrotoxicity in rat models.

Cyclophosphamide (CP) is a chemotherapeutic agent which is extensively used in the treatment of multiple neoplastic and nonneoplastic diseases like breast cancer, lymphomas, systemic lupus erythematosus, and multiple sclerosis. Dose-limiting side effects, mainly nephrotoxicity is a major problem hindering its use in the clinical practice. CP induces nephrogenic syndrome of inappropriate antidiuresis mostly via the activation of arginine vasopressin V2 receptors. Moreover, CP produces reactive metabolites which is responsible for augmentation of lipid peroxidation and oxidative stress. Tolvaptan (TOL) is a selective vasopressin V2 receptor antagonist used in the treatment of clinically significant hyponatremia, volume overload in heart failure, and liver cirrhosis with edema. The present study aimed to investigate the potential protective effect of TOL in CP-induced nephrotoxicity. Twenty-four adult male albino rats were randomly divided into four groups: the control group, TOL group that treated daily with tolvaptan (10 mg/kg/d, orally), CP group where CP was administered intraperitoneally 75 mg/kg on days 3, 4, 5, 19, 20, and 21 of study, and the CP + TOL group where animals were treated with TOL daily with (10 mg/kg/d, orally) for 22 days with concomitant administration of CP as described before. Coadministration of TOL with CP induces significant improvement in the level of urine volume, serum Na+, serum osmolarity, urinary creatinine, and free water clearance in addition to significant reduction of body weight, serum creatinine, urea, serum K+, blood pressure, urine osmolarity, and the fractional excretion of sodium as compared to CP-treated group. In addition, coadministration of TOL significantly reduced MDA, the marker of lipid peroxidation, and different pro-inflammatory cytokines. Histopathological changes showed improvement in the signs of nephrotoxicity with the coadministration of TOL. Also, co-treatment with TOL significantly decreased the level of markers of apoptosis as caspase-3 and Bax with increased expression of antiapoptotic Bcl-2 in renal tissue as compared to CP-treated group.

Active form of vitamin D analogue mitigates neurodegenerative changes in Alzheimer's disease in rats by targeting Keap1/Nrf2 and MAPK-38p/ERK signaling pathways.

BACKGROUND: The nuclear factor erythroid2-related factor2 (Nrf2), a chief transcriptional regulator of antioxidant response element (ARE), is considered a promising target for the prevention of Alzheimer's disease (AD). Vitamin D has been recognized to have a crucial role in improving AD cognitive functions. The present study was conducted to evaluate the effects of active vitamin D analogue, Maxacalcitol, on Keap1-Nrf2 signaling pathway in experimental Alzheimer's disease in rats. MATERIALS AND METHODS: The study was conducted on thirty female white albino rats divided equally into 3 groups: control group, Alzheimer group induced by Lipopolysaccharide and Alzheimer group treated with active vitamin D3 analogue, Maxacalcitol. The following parameters were assessed in rat brain tissues: Gene expression of Nrf2, Keap1 and MAF by RT-PCR, protein levels of phosphorylated MAPK-38p and ERK1/2 by Western Blot Technique, estimation of HO-1, Amyloid ß, p-Tau levels and serum levels of TNFα, IL-10 and total 25-hydroxyvitamin D, serum calcium levels, GSH and MDA levels were also estimated in addition to cognitive function tests and histo-pathological examination of rat brain tissues. RESULTS: In Alzheimer group, there was a significant deficit in cognition along with down-regulation of gene expression of Nrf2 and the protein levels of its downstream antioxidant effectors (HO-1 and GSH) with increased levels of the lipid peroxidation biomarker MDA. Also, there was increased neuro-inflammation as evidenced by increased levels of TNFα and decreased levels of IL-10. Moreover, there were increased amyloid ß load and enhanced levels of phosphorylation of MAPK-38 and ERK1/2 leading to hyperphosphorylation of Tau protein. In addition, there were decreased serum levels of both total 25-hydroxyvitamin D and calcium. Treatment with vitamin D3 analogue, Maxacalcitol significantly improved cognitive dysfunction and histopathological picture of the brains of Alzheimer rats. Also, Vitamin D analogue significantly increased expression of Nrf2 and its downstream effectors (HO-1 and GSH), improved serum levels of total 25-hydroxyvitamin D and calcium, decreased neuro-inflammation and Amyloid ß load as well as hyperphosphorylation of MAPK-38, ERK1/2 and tau proteins were also observed. Therefore, these data suggest that vitamin D analogue, Maxacalcitol could be used as a therapeutic agent in treatment of Alzheimer disease.