Alpha Ketoglutarate: A Novel Therapeutic Approach for ALS

**Alpha-Ketoglutarate: A Novel Therapeutic Approach for ALS**.

**Introduction**.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that affects motor neurons in the brain and spinal cord. Motor neurons are responsible for transmitting signals from the brain to muscles, allowing for voluntary movement. In ALS, these motor neurons gradually deteriorate and die, leading to muscle weakness, paralysis, and eventually respiratory failure..

Currently, there is no cure for ALS, and treatment options are limited. Riluzole and edaravone are two drugs approved by the FDA for ALS; however, their therapeutic efficacy is modest, and they do not halt or reverse the progression of the disease. Therefore, there is a pressing need for new and effective therapies for ALS..

**Alpha-Ketoglutarate (AKG)**.

Alpha-ketoglutarate (AKG) is a naturally occurring metabolite that plays a crucial role in cellular metabolism, particularly in the Krebs cycle, which is the primary energy-generating pathway in cells. AKG has been shown to have neuroprotective effects in various models of neurodegenerative diseases, including ALS..

**Neuroprotective Effects of AKG in ALS**.

Several mechanisms contribute to the neuroprotective effects of AKG in ALS:.

* **Antioxidant activity:** AKG has antioxidant properties and can scavenge free radicals, which are highly reactive molecules that can damage cells and contribute to neurodegeneration..

* **Anti-excitotoxicity:** Excitotoxicity, the excessive activation of glutamate receptors, is a major contributor to neuronal death in ALS. AKG can inhibit excitotoxicity by reducing the release of glutamate and blocking the overactivation of glutamate receptors..

* **Mitochondrial protection:** Mitochondria are the energy powerhouses of cells. AKG can protect mitochondria from damage and dysfunction, which is a common feature of neurodegenerative diseases..

* **Histone deacetylase inhibition:** Histone deacetylases (HDACs) are enzymes that regulate gene expression. AKG can inhibit HDACs, leading to changes in gene expression that promote neuronal survival and protect against neurodegeneration..

**Clinical Studies**.

Several clinical trials have investigated the potential therapeutic benefits of AKG in ALS. In a phase IIa clinical trial, AKG was found to be safe and well-tolerated in patients with ALS, and it demonstrated modest improvements in muscle strength and function..

A phase III clinical trial, known as the RESCUE-ALS trial, is currently underway to evaluate the efficacy and safety of AKG in patients with ALS. The trial is expected to be completed in 2024..

**Conclusion**.

Alpha-ketoglutarate (AKG) is a promising novel therapeutic approach for ALS. Its neuroprotective properties, including antioxidant activity, anti-excitotoxicity, mitochondrial protection, and histone deacetylase inhibition, suggest that it may be a potential disease-modifying therapy for ALS. Clinical trials are ongoing to further evaluate the efficacy and safety of AKG in patients with ALS, and the results of these trials will provide valuable insights into the potential of AKG as a novel treatment for this devastating disease..