Abstract
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is the most common adultonset motor neuron disease, with a lifetime risk of 1 in 2000 [1] and a worldwide incidence of 1–3 new cases per 100,000 individuals [2]
Blood glucose was not significantly different between the diet groups, while the blood bHB was 53% higher in ketogenic diet (KD) and 52% higher in KD+Deanna Protocol (DP) compared to standard rodent diet (SD) (Table 4)
This study demonstrated that the Deanna Protocol (DP) supplementation added to a standard or ketogenic rodent diet improved motor function, delayed neurological deficits, and extended survival in superoxide dismutase 1 (SOD1)-G93A mouse model of ALS
Summary
Amyotrophic Lateral Sclerosis (ALS) is the most common adultonset motor neuron disease, with a lifetime risk of 1 in 2000 [1] and a worldwide incidence of 1–3 new cases per 100,000 individuals [2]. Symptoms of ALS include spasticity, hyperreflexia, generalized weakness, fasciculations, muscle atrophy, and paralysis resulting in impaired respiratory function [3,4]. This leads to death within 3–5 years of onset, most commonly from respiratory failure [3]. Pathological hallmarks of ALS include mitochondrial dysfunction, increased oxidative stress, glutamate excitotoxicity, [10,11], proteinopathy, glutaminergic dysregulation, metabolic dysregulation, and motor neuron death [9]. These disrupted cellular functions represent discrete targets for therapies that may ameliorate disease progression
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