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

Medicinal Chemistry Neurology Chemistry Biochemistry Basic Medical Sciences Life Sciences Immunology Medicine Cell Biology
Amyotrophic Lateral Sclerosis Neurodegeneration Multifactorial Mechanisms Drug Combination Therapy Motor Neuron Protection

Report on ALS Treatment Study: Exploring the Multifaceted Mechanisms of Nebivolol and Donepezil

Background and Research Objectives

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of motor neurons in the spinal cord and brain, leading to severe muscle atrophy, functional decline, and eventual death from respiratory failure. The two FDA-approved drugs for ALS, Riluzole and Edaravone, only extend survival by a few months and offer limited functional improvement. This underscores the urgent need for innovative therapies. The multifactorial pathophysiology of ALS, encompassing inflammatory responses, glutamate excitotoxicity, and oxidative stress, complicates drug development.

This study, led by Dr. Noah Biotech Inc., aims to develop a combination drug targeting multiple pathological mechanisms to slow ALS progression. Published in Neurotherapeutics (2023, Vol. 20), the study explores the potential of a drug combination, Nebivolol and Donepezil (referred to as Nebivolol-Donepezil), for ALS treatment.

Research Workflow and Experimental Design

The study utilized artificial intelligence (AI) drug screening based on the genomics of ALS patients and drug pharmacogenomics data. Through weighted correlation network analysis (WGCNA), pathological networks were constructed, leading to the identification of 627 drug candidates. A multi-stage screening process narrowed this to Nebivolol-Donepezil. The drug combination was then tested in vitro and in vivo to validate its therapeutic potential.

Experimental Methodology

  1. Data Analysis and Drug Screening Using AI algorithms, seven ALS gene expression datasets (six microarrays, one RNA-seq) were analyzed, integrating drug-induced expression data to calculate the probability of reversing pathological networks. Nebivolol (an antihypertensive) and Donepezil (an anti-dementia drug) were selected as a combination for their potential.

  2. In Vitro Experiments

    • Anti-Inflammatory Effects: Using BV-2 mouse microglial cells, the combination was tested for inhibition of LPS-induced inflammation. Results showed significant reductions in NO levels and pro-inflammatory factors (e.g., iNOS, IL-1β, TNF-α), surpassing the effects of individual drugs.
    • Neuroprotection: The combination protected neurons from glutamate-induced excitotoxicity in mouse cortical neurons via the PI3K-AKT pathway.
    • Neuronal Differentiation: The combination promoted differentiation of neural progenitor cells (NPCs) into motor neurons, increasing expression of the motor neuron marker HB9 and neurotrophic factors like BDNF and GDNF.

  3. In Vivo Experiments

    • ALS Mouse Model Treatment: Using SOD1-G93A transgenic mice, low-dose Nebivolol-Donepezil improved motor function, reduced spinal motor neuron loss, and alleviated muscle atrophy. High-dose treatment delayed disease onset and extended survival.

Experimental Results

  1. Anti-Inflammatory Mechanisms The combination inhibited NF-κB nuclear translocation, reducing pro-inflammatory cytokine levels, indicating effective modulation of ALS-related neuroinflammation.

  2. Protection Against Excitotoxicity The drug combination significantly enhanced neuronal survival under glutamate-induced toxicity, with effects mediated by the PI3K pathway.

  3. Motor Neuron Differentiation The drugs elevated neurotrophic factors and promoted NPC differentiation into motor neurons, supporting potential network repair in ALS.

  4. Muscle Atrophy Prevention Nebivolol-Donepezil reversed ALS mouse muscle atrophy, increasing myofiber size and reducing atrophic fibers.

  5. Improved Survival and Quality of Life High-dose treatment significantly delayed disease onset and prolonged survival in ALS mice, demonstrating comprehensive therapeutic benefits.

Significance and Implications

This study proposes a novel multitargeting strategy for ALS treatment using a combination drug. Nebivolol-Donepezil demonstrated efficacy across key ALS pathologies, including inflammation control, neuroprotection, neuronal repair, and muscle preservation. By addressing the multifactorial nature of ALS, this combination has the potential to overcome the limitations of current single-target therapies and pave the way for clinical trials.

Through its ability to target diverse ALS mechanisms, Nebivolol-Donepezil holds promise for improving both the quality of life and survival outcomes for ALS patients.