Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.

Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation

“…Kaempferide and kaempferol are active ingredients of Brazilian green propolis that possess antioxidative properties and were shown to prevent SOD1 intracellular aggregates in a mutant SOD1-induced N2A cellular model [ 226 ]. Other studies also reported that the treatment with antioxidants (e.g., fisetin or protocatechuic acid) improves survival rate, attenuates motor impairment, reduces astrogliosis and microgliosis in the spinal cord, protects the spinal motor neurons from apoptosis, and regulates redox homeostasis by lowering the levels of both mutant and wild-type human SOD1 [ 227 , 228 ].…”

Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities

“…Protocatechuic acid, a major metabolite of anthocyanin, is reported to inhibit the aggregations of Aβ and α-synuclein and ultimately recovers the cell viability of PC-12 cells [185]. In addition, protocatechuic acid also lessens the severity of pathological symptoms and slows down the progression of disease in the mouse model of ALS [186]. Moreover, the ability of anthocyanins to cross the BBB suggests that anthocyanins may be a promising drug for the treatment of neurodegenerative diseases [187].…”

Anthocyanins in Chronic Diseases: The Power of Purple

“…Amyotrophic lateral sclerosis is characterised by neuron apoptosis followed by skeletal muscle atrophy [ 181 ] with proposed mechanisms including oxidative stress, neuroinflammation and mitochondrial dysfunction. While no reports on the treatment of human amyotrophic lateral sclerosis with anthocyanins have been found, the anthocyanin metabolite, protocatechuic acid, sustained neuromuscular function with improved motor function and decreased gliosis in the hSOD1 G93A mouse model of this disease [ 182 ].…”