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A Systematic Review cells Review Therapeutic Potential of Complementary and Alternative Medicines in Peripheral Nerve Regeneration: A Systematic Review Yoon-Yen Yow 1,* , Tiong-Keat Goh 1 , Ke-Ying Nyiew 1, Lee-Wei Lim 2,* , Siew-Moi Phang 3,4, Siew-Huah Lim 5, Shyamala Ratnayeke 1 and Kah-Hui Wong 6,* 1 Department of Biological Sciences, School of Medicine and Life Sciences, Sunway University, Petaling Jaya 47500, Malaysia; [email protected] (T.-K.G.); [email protected] (K.-Y.N.); [email protected] (S.R.) 2 Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, L4 Laboratory Block, Hong Kong 3 Institute of Ocean and Earth Sciences, Universiti Malaya, Kuala Lumpur 50603, Malaysia; [email protected] 4 Faculty of Applied Sciences, UCSI University, Cheras, Kuala Lumpur 56000, Malaysia 5 Department of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia; [email protected] 6 Department of Anatomy, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia * Correspondence: [email protected] (Y.-Y.Y.); [email protected] (L.-W.L.); [email protected] (K.-H.W.); Tel.: +603-7491-8622 (Y.-Y.Y.); +852-3917-6830 (L.-W.L.); +603-7967-4729 (K.-H.W.) Citation: Yow, Y.-Y.; Goh, T.-K.; Nyiew, K.-Y.; Lim, L.-W.; Abstract: Despite the progressive advances, current standards of treatments for peripheral nerve Phang, S.-M.; Lim, S.-H.; injury do not guarantee complete recovery. Thus, alternative therapeutic interventions should Ratnayeke, S.; Wong, K.-H. be considered. Complementary and alternative medicines (CAMs) are widely explored for their Therapeutic Potential of therapeutic value, but their potential use in peripheral nerve regeneration is underappreciated. Complementary and Alternative The present systematic review, designed according to guidelines of Preferred Reporting Items for Medicines in Peripheral Nerve Systematic Review and Meta-Analysis Protocols, aims to present and discuss the current literature Regeneration: A Systematic Review. on the neuroregenerative potential of CAMs, focusing on plants or herbs, mushrooms, decoctions, Cells 2021, 10, 2194. https://doi.org/ and their respective natural products. The available literature on CAMs associated with peripheral 10.3390/cells10092194 nerve regeneration published up to 2020 were retrieved from PubMed, Scopus, and Web of Science. According to current literature, the neuroregenerative potential of Achyranthes bidentata, Astragalus Academic Editor: FengRu Tang membranaceus, Curcuma longa, Panax ginseng, and Hericium erinaceus are the most widely studied. Various CAMs enhanced proliferation and migration of Schwann cells in vitro, primarily through Received: 24 July 2021 Accepted: 20 August 2021 activation of MAPK pathway and FGF-2 signaling, respectively. Animal studies demonstrated Published: 25 August 2021 the ability of CAMs to promote peripheral nerve regeneration and functional recovery, which are partially associated with modulations of neurotrophic factors, pro-inflammatory cytokines, and Publisher’s Note: MDPI stays neutral anti-apoptotic signaling. This systematic review provides evidence for the potential use of CAMs in with regard to jurisdictional claims in the management of peripheral nerve injury. published maps and institutional affil- iations. Keywords: complementary and alternative medicines; natural products; peripheral nerve injury; nerve repair; nerve regeneration; functional recovery Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. 1. Introduction This article is an open access article Peripheral nerve injury (PNI) can result in partial or total loss of motor, sensory and distributed under the terms and autonomic functions at denervated regions, leading to temporary or life-long disability [1]. conditions of the Creative Commons In addition to reduced quality of life, functional deficits from PNI have a substantial Attribution (CC BY) license (https:// economic impact on the affected individuals [2]. A recent study found that, over nine years creativecommons.org/licenses/by/ (from 2009 to 2018), more than 550,000 individuals were afflicted by PNI in the United 4.0/). Cells 2021, 10, 2194. https://doi.org/10.3390/cells10092194 https://www.mdpi.com/journal/cells Cells 2021, 10, 2194 2 of 35 States. Moreover, the incidence rate has more than doubled throughout that period of time [3]. Such injuries are primarily due to vehicular and traumatic accidents, lacerations, and iatrogenic causes [4–6]. Despite progressive advances in our understanding of the processes and mecha- nisms of nerve injury, effective nerve repair and regeneration approaches that ensure complete functional recovery remain scarce [7]. Nerve autograft is considered the gold standard for repairing peripheral nerve defects [8]. However, this method is restricted by limited donor nerves and donor site morbidity, while successful recovery rates remain unsatisfactory [9]. Consequently, alternative strategies for enhancing nerve repairs have been proposed, including the application of nerve conduits and the addition of growth factors [10,11]. Likewise, the exploration of novel therapeutics, even combinatorial therapies, capable of enhancing axonal regeneration and promoting functional recovery, are of great interest. PNI often results in neuropathic pain, and when conventional treatments are inade- quate in providing relief, patients may turn to complementary and alternative medicines (CAMs), such as herbal medicines and nutritional supplements [12]. Indeed, medicinal plants, including the Acorus calamus [13], Curcuma longa [14], and Ginkgo biloba [15], have displayed ameliorating effects in animal models of neuropathic pain. Research on the potential of medicinal plants in the treatment of PNI is prompted by the notion that plants are great sources of natural products (NPs), which are small molecules produced by living organisms. Many NPs are the focus of drug development, as it is generally believed that they are largely devoid of adverse effects compared to synthetic drugs [16,17]. NPs also have the advantage of being evolutionary-driven, thus they are more likely to possess tremendous chemical and structural diversity that facilitates efficient engagement with biologically relevant targets and receptors, making them more biologically active [18]. In fact, many small-molecule drugs that have been approved by regulatory agencies were derived from natural sources [19], including Taxol from Taxus brevifolia [20] and Vinblastine from Catharanthus roseus [21]. However, compared to the extensive research on naturally derived products for other non-communicable and infectious diseases, NPs remain largely unexplored in the field of nerve repair and regeneration. A review published nearly half a decade ago has shed light on the neuroprotective effects of NPs in PNI models [22]. This review presents current research findings and evaluates the role of CAMs, focusing on plants or herbs, mushrooms, and decoctions, as well as their NPs, in peripheral nerve regeneration, to highlight their therapeutic potential for the management of PNI. 2. Materials and Methods This systematic review was designed according to guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) [23]. 2.1. Search Strategy and Data Extraction A literature search was performed to find all relevant publications up to 25 October 2020 across three electronic databases, PubMed, Scopus, and Web of Science. The fol- lowing keywords were used to search each respective database: ((“peripheral* nerve* regenera*” OR “peripheral* nerve* repair*” OR “neuroregenera*”) AND (“alga*” OR “seaweed*” OR “plant” OR “natural product*” OR “mushroom” OR “Basidiomycete*” OR “herb*” OR “Traditional Chinese Medicine*” OR “alternative medicine” OR “com- plementary medicine*”)). Cells 2021, 10, x FOR PEER REVIEW 3 of 38 Cells 2021, 10, 2194 3 of 35 2.2. Eligibility Criteria 2.2. EligibilityResearch Criteriaarticles describing the use of plants or herbs, mushrooms, algae, decoction, and theirResearch natural articles products describing in peripheral the use nerve of plants repair or and herbs, regeneration, mushrooms, written algae, in decoction, English, and theirhaving natural full-text products availability in peripheral were consid nerveered. repair Articles and regeneration, not representing written original in English, re- searchand having studies full-text and NPs availability derived were from considered. sources other Articles than not plants, representing herbs, algae, original and research mush- roomsstudies were and NPsexcluded derived (e.g., from Lumbricus sources otherrubellus than—earthworm). plants, herbs, Retrieved algae, and articles mushrooms were screenedwere excluded based (e.g.,on theirLumbricus title, abstract, rubellus and—earthworm). full-text to determine Retrieved their articles eligibility were for screened inclu- sionbased in onthis their review. title, abstract, and full-text to determine their eligibility for inclusion in this review. 3. Results 3. Results A preliminary search across the three databases yielded 560 records, of which 215 were Aduplicates preliminary (Figure search 1). across Together the three with databases18 other records yielded id 560entified records, by of other which means, 215 were the remainingduplicates articles (Figure 1were). Together screened with based 18 other on the records eligibility identified criteria, by resulting other means, in 289 the addi-
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