Therapeutic Effects of Combination of Nebivolol and Donepezil: Targeting Multifactorial Mechanisms in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1G93A mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.

Evaluation of hepatoprotective effect of Nebivolol and sodium copper Chlorophyllin on CCL4-induced hepatotoxicity in mice.

OBJECTIVE: In this study, the protective effect of sodium copper chlorophyllin and nebivolol was evaluated in a mice model of CCL4 induced hepatotoxicity. Silymarin was used as a traditional hepatoprotective drug. MATERIALS AND METHODS: Thirty (30) mice were used as they were divided into five groups: the first group was the control group which received distilled water + olive oil, the second group which received 1.5 ml/kg of CCl4 diluted in olive oil three times a week, the third group which received CCl4 + Silymarin 50 mg/kg/day, the fourth group which received CCl4 + nebivolol 4 mg/kg/day, and the fifth group which received 1.5 ml/kg of CCl4+ Cu-chlorophyllin 50 mg/kg/day. The drugs were given by intraperitoneal route for 5 weeks. The detection, quantification of CCl4 induced hepatotoxicity and possible protective effect of either silymarin, nebivolol, or sodium copper chlorophyllin were assessed using biochemical analysis of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein, lipid profile, an assay of oxidants and antioxidants, assay of interleukin 6 (IL6) and tumor necrosis factor-alpha (TNF-α), and histopathological examination. RESULTS: The administration of carbon tetrachloride (CCl4) produced pronounced liver impairment. It significantly increased ALT, AST, ALP, malondialdehyde, and serum nitric oxide levels compared to normal control group besides a decrease in total protein, serum catalase, tissue SOD, and GSH levels. IL-6 and TNF-α levels were significantly higher while total cholesterol was significantly lower in mice receiving CCL4 compared to the normal control group. CCL4 induced severe hyperemia and congestion inside the portal area with leukocytic infiltration, hepatic degeneration, and bridge fibrosis. CONCLUSIONS: Co-administration of either silymarin, nebivolol, or sodium copper chlorophyllin with CCl4 was able to ameliorate up to almost contradict CCl4 induced hepatic injury through their anti-inflammatory and antioxidant activities.