Oxidative Stress in Spinocerebellar Ataxia Type 3 and Its Attenuation by Herbal Remedies in Traditional Chinese Medicine: A Systematic Review

Abstract

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder that gives rise to motor incoordination and progressive functional disabilities. Although pharmacological interventions have revealed promising prospects in the management of SCA3, adverse effects may become unbearable. The use of herbal remedies in traditional Chinese medicine (TCM) may serve as potential alternative medicines to delay the progression of the disease. This systematic review is intended to identify, appraise, and summarize the findings of studies pertaining to the therapeutic roles of herbal remedies in TCM targeting oxidative stress in the management of SCA3. A literature search for relevant articles published from 1 January 2013 to 30 June 2023 in three databases, namely PubMed, Web of Science, and Scopus, was carried out according to the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of ten preclinical studies met the inclusion criteria of the systematic review. We recognized the therapeutic potential of Brassica napus, Codonopsis pilosula, Curcuma sp., Gardenia jasminoides, Gastrodia elata, Ginkgo biloba, Glycyrrhiza inflata, Hericium erinaceus, Hyptis sp., Paeonia lactiflora, Panax ginseng, Poria cocos, Pueraria lobata, Rehmannia glutinosa, and Scrophularia ningpoensis. We identified the types of preclinical models expressing polyglutamine (polyQ) expanded mutant protein (mATXN3), inducers of oxidative stress that mimic the SCA3 pathogenesis, and effective doses of the herbal remedies. The modes of action contributing to the attenuation of oxidative stress are activation of antioxidant pathways, ubiquitin-proteasome system and autophagy, regulation of apoptosis, proinflammatory signaling pathway and chaperones, regulation of mitochondrial function and biogenesis, and restoration of neurotransmission and synaptic plasticity. In conclusion, herbal remedies in TCM may possibly delay the progression of SCA3, therefore providing justification for clinical trials.

Keywords: antioxidant defense system; mutant ATXN3; oxidative stress; spinocerebellar ataxia type 3; traditional Chinese medicine.

Figure 1

Oxidative stress in the pathogenesis of SCA3. (A) In normal condition, the activation of FOXO4, BCL2L1, and NFE2L2 is essential regulators of cellular homeostasis. (B) In SCA3, mATXN3 protein inhibits he activation of FOXO4, BCL2L1, and NFE2L2, causing enhanced ROS production, mitochondrial dysfunction, and disruption of homeostasis, leading to cell death.

Figure 2

Mitochondrial dysfunction in the pathogenesis of SCA3. A: ATXN3 protein is necessary for the regulation of transcription, proteasome-, and autophagy-mediated protein degradation pathways, the removal of ubiquitin from parkin, DNA damage repair, and cytoskeletal dynamics. It functions as a deubiquitinating enzyme in the regulation of parkin prior to the degradation of impaired mitochondrial proteins. B: Full-length mATXN3 protein decreases the mtDNA number, disrupts the assembly of complex II, reduces the BCL2 protein, and prolongs mPTP opening, leading to mitochondrial dysfunction and mitochondrial-mediated cell death. C: Truncated mATXN3 protein enhances mitochondrial fission and decreases the mitochondrial fusion and MMP, leading to mitochondrial dysfunction, an accumulation of ROS, and eventually, apoptosis.

Figure 3

Alteration of DNA damage response in the pathogenesis of SCA3. (A) In normal conditions, the ATXN3 protein stabilizes MDC1 to initiate remodeling of damaged chromatin and promote the recruitment of PNKP, CHEK1, and TP53 to induce cell-cycle arrest, ensuring DNA repair and cell survival. (B) In SCA3, the mATXN3 protein inhibits PNKP and activates TP53-mediated neuronal death, causing mitochondrial pathway of apoptosis.

Figure 4

PRISMA flow chart for the identification and selection of relevant studies.

Figure 5

The herbal remedies in TCM and their corresponding bioactive compounds in the management of SCA3.

Figure 6

Modes of action of herbal remedies in TCM in the management of SCA3: Activation of antioxidant pathways, activation of UPS and autophagy, regulation of apoptosis, proinflammatory signaling pathway, and chaperones, regulation of mitochondrial function and biogenesis, and restoration of neurotransmission and synaptic plasticity.