PGC1α: an emerging therapeutic target for chemotherapy-induced peripheral neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN)-mediated paresthesias are a common complication in cancer patients undergoing chemotherapy. There are currently no treatments available to prevent or reverse CIPN. Therefore, new therapeutic targets are urgently needed to develop more effective analgesics. However, the pathogenesis of CIPN remains unclear, and the prevention and treatment strategies of CIPN are still unresolved issues in medicine. More and more studies have demonstrated that mitochondrial dysfunction has become a major factor in promoting the development and maintenance of CIPN, and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC1α) plays a significant role in maintaining the mitochondrial function, protecting peripheral nerves, and alleviating CIPN. In this review, we highlight the core role of PGC1α in regulating oxidative stress and maintaining normal mitochondrial function and summarize recent advances in its therapeutic effects and mechanisms in CIPN and other forms of peripheral neuropathy. Emerging studies suggest that PGC1α activation may positively impact CIPN mitigation by modulating oxidative stress, mitochondrial dysfunction, and inflammation. Therefore, novel therapeutic strategies targeting PGC1α could be a potential therapeutic target in CIPN.

Keywords

chemotherapy-induced peripheral neuropathy mitochondrial biogenesis mitochondrial dysfunction oxaliplatin oxidative stress paclitaxel PGC1α

Introduction

Cancer is one of the top death causes across the globe, and despite the enormous efforts to implement novel chemotherapy strategies, the disease remains one of the major concerns worldwide. According to the International Agency for Research on Cancer (IARC), it is estimated that over 19.3 million new cancer cases were diagnosed in 2020, followed by 10.0 million deaths.^1,2 With the rapid development of modern cancer diagnosis and treatment technology, cancer patients’ survival rate has increased year by year, and the survival period has been prolonged.³ Statistical analysis shows that the cancer mortality rate in the United States is decreasing at an annual rate of 1.5%, and the overall reduction in 2020 is 29% compared with 1991. Among them, the 5-year survival rate of prostate cancer and female breast cancer is as high as 90%.⁴ Consistently, the 5-year survival rate of cancer patients in China also showed a significant upward trend.⁵ Cancer is gradually changing from a ‘terminal illness’ to a chronic disease, and the goal of cancer treatment is changing from ‘survival’ to ‘quality survival’. Chemotherapy is the most extensively used approach for cancer treatment, while chemotherapy-induced peripheral neuropathy (CIPN) is the major side effect that hinders cancer treatment. Up to 80% of chemotherapy patients develop CIPN, and 40–60% of the patients have to terminate or delay the treatment.⁶

Chemotherapy-induced peripheral neuropathy

Many first-line cytotoxic agents inducing peripheral neuropathy have been used in solid tumors and hematological malignancies, including blockbuster anti-tumor agents, paclitaxel, lenalidomide, and oxaliplatin. CIPN severely limits the use of chemotherapy agents and is a common cause of chemotherapy discontinuation. Besides, immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and cytotoxic-T-lymphocyte-antigen-4 (CTLA4) have recently been found to cause similar neurological side effects.^7,8 CIPN symptoms initially manifested as typical ‘glove and stocking’ neuropathy, symmetrical numbness of the extremities, with pinning and burning paresthesias, and then progressed to sensory and motor disturbances, and eventually to muscle weakness, difficulty moving, burning sensations, and severe pain in the extremities.⁶ Some patients suffer CIPN even if their cancer has been cured, such as numbness or burning pain in the hands and feet for years, with major and permanent consequences for life barriers. However, CIPN does not respond well to conventional analgesics and is extremely difficult to treat. There is no specific drug that can prevent and treat CIPN in clinical practice.⁹ The American Society of Clinical Oncology (ASCO) acknowledged this dilemma, recommending only duloxetine for the relief of CIPN symptoms in its published clinical practice guidelines on the prevention and management of CIPN. The difficulties faced in the development of CIPN drugs mainly include (1) The pathogenic mechanism of CIPN is still unclear; (2) Disease factors such as cancer increase the complexity of CIPN treatment as cancer and CIPN can synergize on a common signaling pathway; (3) The prevention and treatment of CIPN should not affect the anticancer effect of chemotherapy. Therefore, elucidating the pathogenesis of CIPN and developing specific agents for CIPN prevention and treatment have very important scientific significance and clinical practical value. Prevention and treatment of CIPN represent a critical unmet medical need. This demand has also shifted from academic research to industrial investment. In August 2018, Pfizer, Eli Lilly, and AbbVie have jointly invested US$31 million to launch drug development for the prevention of peripheral neuropathy and cognitive impairment caused by chemotherapy.¹⁰ Therefore, the prevention and treatment of CIPN is a medical need that needs to be urgently met.

Mitochondrial dysfunction in CIPN

The pathogenesis of CIPN induced by chemotherapy mainly includes, (1) abnormal expression and activation of cell membrane receptors and ion channels, (2) changes in intracellular signal transduction, (3) mitochondrial damage and oxidative stress, (4) the activation of glial cells and the generation of neuroinflammation eventually lead to the sensitization of peripheral sensory neurons and the damage of neurons and nerve fibers.⁶ Among them, mitochondrial dysfunction is reported to be significant pathogenesis of CIPN, which corresponds to the clinical manifestations.^11–15

Mitochondria, as highly active organelles, carry out their own ‘renewal and regeneration’ through biosynthesis, division/fusion, and autophagy to maintain their morphological and functional integrity. Disruption of mitochondrial homeostasis and subsequent mitochondrial dysfunction plays a key role in peripheral neuropathy caused by multiple pathological factors.^16–19 Accumulating evidence indicates that many chemotherapeutic agents cause mitochondrial damage in the peripheral sensory nerves by disrupting mitochondrial structure and bioenergetics, increasing nitro-oxidative stress, and altering mitochondrial transport and fission, fusion, and mitophagy. The mitotoxicity theory of CIPN has proposed that the abnormal and dysfunctional mitochondria in sensory neurons are led to axonal growth defects and the loss of intraepidermal nerve fibers, which in turn increased spontaneous discharge and the sensitization of peripheral sensory neurons and the central nervous system that promote the establishment of chronic pain state.²⁰ Mitochondrial damage has been reported to be involved in the pathological process of paclitaxel-induced CIPN. Flatters et al. found that mitochondrial swelling and vacuolization in both C-fibers and myelinated axons are the main neuropathological features for paclitaxel-induced painful peripheral neuropathy.²¹ Besides, a clinical study has demonstrated that mitochondrial swelling and vacuolization were observed in sensory axons by electron microscopy in sural nerve biopsies from CIPN patients induced by paclitaxel²² and docetaxel.²³ This phenomenon has also been observed in C-fiber and A-fiber of oxaliplatin, and bortezomib-induced CIPN rats.^24,25 In addition, paclitaxel-induced changes in neuronal mitochondria in C fiber and myelinated axons are correlated to paclitaxel-induced pain syndrome.²¹

Recent research shows that mitochondrial swelling and vacuolization in C-fibers and myelinated axons disrupt the maintenance of the proton gradient, impair mitochondrial ATP production, and result in severe energy insufficiency, and increased reactive oxygen species (ROS) production in neurons.^26,27 Chemotherapy-evoked changes in bioenergetics are also associated with decreased ATP production.^28,29 The maximal respiration and respiratory ability were significantly decreased in dorsal root ganglia (DRG) neurons of paclitaxel-induced CIPN rats. Duggett et al. found enhanced basal glycolysis and maximal glycolytic ATP production in peripheral sensory neurons during peak pain in absence of altered respiration or respiratory capacity, suggesting the energy supplement of sensory neurons switched from relying on oxidative phosphorylation through less efficient glycolysis.²⁹ Moreover, the function of mitochondrial was also decreased in complex I-stimulated and complex II-stimulated respiration in sciatic nerves from paclitaxel-, oxaliplatin-, and bortezomib-induced CIPN rats.^25,28 It has been reported that a complex III inhibitor, antimycin A significantly prevented the development of paclitaxel-induced CIPN, but had no therapeutic effect on CIPN.³⁰ Mitochondrial DNA damage has been demonstrated to be a novel process for the induction of CIPN induced by chemotherapeutic agents.³¹ Mannelli et al. reported that the DNA oxidation product 8-Hydroxy-2’-deoxyguanosine (8-OH-dG) has increased in the sciatic nerve and spinal cord with a rat model of oxaliplatin-induced CIPN.³²

The therapies targeting chemotherapy-induced mitochondrial oxidative stress have the potential to protect mitochondrial function and alleviate neuropathological damage. Antioxidant pharmacological strategies using ROS/RNS scavengers, superoxide dismutase (SOD) mimetics, and peroxynitrite decomposition catalysts have shown success in attenuating chemotherapy-induced neurotoxic effects in cellular and animal models, including n-tert-Butyl-a-phenylnitrone (PBN)-a global free-radical scavenger,³³ 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL)-a nonselective nitroxyl antioxidant,³⁴ the active metabolite of amifostine [N-2-mercaptoethyl]-1-3-diaminopropane (WR-1065), a ROS/RNS scavenger,³⁵ and the SOD mimetic, polyamine-polycarboxylate-MnII complex 4,10-dimethyl-1,4,7,10 tetraazacyclododecane-1,7-diacetic acid MnII (MnL4).³⁶ Other strategies attempt to protect against nerve damage by indirectly hindering mitochondrial oxidative stress. Meclizine, a histamine H1 receptor antagonist, has been reported to switch cells to glycolysis and pentose phosphate pathways to improve ATP production and neurite outgrowth in DRG neurons treated with cisplatin.³⁷ Recent research has shown that oxidative stress can drive matrix metalloproteases 9 (MMP9) mitochondria translocation and induce mitochondria dysfunction,³⁸ while intrathecal administration of the monoclonal antibody of MMP9 attenuated ROS production in the DRG and resulted in decreased IENF loss and paclitaxel-induced neuropathic pain in mice.³⁹ Targeting the oxidative stress-sensitive poly (ADP-ribose) polymerase (PARP)/p53 pathway has been reported to prevent mitochondrial dysfunction and neural damage. Pifithrin-μ, a p53 inhibitor, has been reported to prevent mitochondrial damage in the DRG by preventing the accumulation of p53 in the mitochondria and protects against paclitaxel- and cisplatin-induced mechanical allodynia and loss of intraepidermal nerve fiber in mice.^40,41 Therefore, promoting and repairing mitochondrial function may be a new strategy for the treatment of CIPN.

PGC1α, a master coactivator, triggers mitochondrial biogenesis in CIPN

Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC1α) was first discovered in brown adipose tissue as a PPARγ coactivator in response to cold stimulation.⁴² The major function of PGC1α is to regulate mitochondrial biosynthesis to promote aerobic metabolism and resist oxidative stress, and its expression level directly determines mitochondrial function and self-renewal level.^43,44 PGC1α is highly expressed in multiple tissues, including brown adipose tissue, liver, heart, pancreas, skeletal muscle, and kidney,^45,46 as well as in the nervous system, including the cerebral cortex, spinal cord, and DRG neurons, and mediates various neurological diseases.^43,47 It has been reported that PGC1α regulates the expression of enzymes for ROS detoxifying, such as SOD1 and 2, catalase, and glutathione peroxidase-1.⁴⁸ Besides, PGC1α acts as a coactivator with other transcription factors including the nuclear respiratory factor (NRF), transcriptional factor A mitochondrial (TFAM), and myocyte enhancer factor 2.⁴⁹ The PGC1α-NRF1/2-TFAM axis plays an important role in the regulation of mitochondrial regeneration. PGC1α promotes the expression of TFAM through NRF1/2. TFAM is a key factor in initiating mitochondrial transcription, promoting mitochondrial DNA (mtDNA) replication, and regulating mitochondrial regeneration.⁵⁰ In models of Parkinson’s disease, Alzheimer’s disease, and aging, the expression levels of TFAM and mtDNA are reduced and mitochondrial function is impaired, while overexpression of TFAM in mitochondria is neuroprotective against these neurodegenerative diseases.⁵⁰ A recent study reveals that PGC1α inhibitor SR-18292 reverses the analgesic effect of ZLN005 and abolishes the analgesic effect of formoterol against CIPN.⁵¹

In sensory neurons, AMP-activated protein kinase (AMPK) mediates muscarinic ACh type 1 receptor (M1R) antagonists induced PGC1α and mitochondrial activity to promote neurite outgrowth from adult sensory neurons and to protect animal models against peripheral neuropathy induced by diabetes, the chemotherapeutic agents such as dichloroacetate and paclitaxel, or human immunodeficiency virus (HIV) envelope protein gp120.^52,53 Furthermore, overexpression of PGC1α can increase the number and quality of mitochondria in DRG neurons of diabetic mice.⁵⁴ PGC1α-mediated mitochondrial biogenesis has also been reported to be involved in the attenuation of neuropathic pain at the spinal level in peripheral nerve injury. Activation of PGC1α in the spinal cord attenuates established mechanical allodynia in rats with neuropathic pain.⁵⁵ NRF2 attenuates chronic constriction injury-induced neuropathic pain via the induction of PGC1α-mediated mitochondrial biogenesis in the spinal cord.⁵⁶ In addition, PGC1α also regulates a series of nuclear receptors including the thyroid hormone receptor, and the estrogen receptor.⁴⁹

PGC1α acts as an oxidative stress regulator in CIPN

Intracellular ROS is mainly derived from mitochondrial and excessive production of ROS leads to mitochondrial dysfunction. ROS-induced oxidative stress and the subsequent injury of the myelin sheath, mitochondrial proteins, and antioxidant enzymes in peripheral neurons is a substantial initiator for CIPN.¹³ In vivo study has demonstrated that scavenge ROS inhibited the development of CIPN induced by paclitaxel and bortezomib.^57,58 Elamipretide (SS-31), a mitochondria-targeted antioxidant, attenuated oxaliplatin-induced CIPN.⁵⁹ MitoVitE attenuated the development of paclitaxel-induced mechanical hypersensitivity.⁶⁰ Previous in vivo study has also demonstrated that ROS production was significantly increased in the spinal cord and lumbar DRG after chemotherapeutic agent treatment.^59,61 Besides, ROS levels were also significantly increased in the superficial spinal and DRG neurons in vivo before the onset of paclitaxel-induced mechanical allodynia, suggesting ROS works as an initiating factor.⁶² However, antioxidant enzymes were also enhanced in the DRG and peripheral sensory nerves in CIPN animals.⁶² These data reveal that mitochondrial ROS increase is an initiating factor for the development and maintenance of CIPN (Figure 1).

Figure 1.

The peripheral neuropathological features and mitochondrial dysfunction of dorsal root ganglia (DRG) neurons in chemotherapy-induced peripheral neuropathy (CIPN).

Recent research has shown that the administration of Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, decreases plasma oxidative stress, increases the expression of PGC1α and mitochondrial antioxidant proteins, alleviates mechanical and thermal hypersensitivity, and partially prevents neuronal loss of small unmyelinated intraepidermal nerve fibers. In addition, evodiamine, a plant-derived natural compound, has been reported to prevent paclitaxel-induced loss of mitochondrial membrane potential, increase PGC1α expression in DRG cells, and maintain mitochondrial anti-oxidant functions, and ameliorate paclitaxel-induced neuropathic pain.⁶³ However, the mechanism of PGC1α in mitochondrial anti-oxidative stress in CIPN is still unclear and needs further exploration.

PGC1α acts as a therapeutic target in peripheral neuropathy

PGC1α is increasingly recognized as an important target in the prevention and regulation of CIPN and other forms of neuropathy. A series of literature have reported the potential of natural compounds or molecules to treat CIPN by modulating PGC1α expression or function. Resveratrol has been reported to reduce apoptosis by SIRT1/PGC1α signal pathway, prevent paclitaxel-induced mitochondrial damage, and improve the relevant pain symptoms.⁶⁴ Evodiamine prevented paclitaxel-induced loss of mitochondrial membrane potential and paclitaxel-induced neuropathic pain via regulating PGC1α expression in DRG neurons.⁶³ Ghrelin alleviates paclitaxel-induced CIPN by reducing oxidative stress and enhancing PGC1α expression in mice.⁶⁵ Nuclear sirtuin 1 (SIRT1)/PGC1α signaling has been reported to be involved in the analgesic effect of translocator protein in a rat spinal nerve ligation model.⁶⁶ SIRT1 activation alleviates oxidative damage and enhances PGC1α-NRF1/2-TFAM axis-mediated mitochondrial biogenesis in diabetic neuropathy rats.^67–69 Furthermore, multiple lines of evidence suggest that PGC1α mediates the mitochondrial function promotion and neuroprotection effect of multiple upstream regulators. Berberine exposure augmented PGC1α-mediated mitochondrial biogenesis in DRG neurons in experimental diabetic neuropathy rats.⁷⁰ Impaired AMPK signaling in DRG neurons is associated with PGC1α-mediated mitochondrial dysfunction and peripheral neuropathy in diabetes.⁷¹ Salvianolic acid A application and potassium voltage-gated channel subfamily B member 1 (Kv2.1) inhibition protect the peripheral nerve function in diabetic rats through the regulation of the AMPK/PGC1α pathway.^72,73 Furthermore, overexpression of human TFAM in mice can prevent type 1 diabetes-induced nerve conduction slowdown, improve epidermal fiber loss, and alleviate mechanical hyperalgesia.⁷⁴ As an upstream regulator of TFAM, knockout of PGC1α leads to mitochondrial damage, increases oxidative stress, leads to mitochondrial dysfunction, and exacerbates diabetic neuropathy.⁷⁵ Therefore, promoting mitochondrial regeneration mediated by the PGC1α-NRF1/2-TFAM axis might be a potential approach for exploring the prevention and treatment of diabetic peripheral neuropathy.

In addition, several natural compounds and molecules targeting PGC1α, including resveratrol, evodiamine, berberine, and ghrelin have shown neuroprotective effects against CIPN and diabetic neuropathy in preclinical studies as discussed above, further clinical trials refer to these molecules are highly recommended. The pan-PPAR agonist bezafibrate, ferulic acid, and co-activation of PPARγ and PGC1α with N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine (GW1929) and alpha-lipoic acid have shown strong therapeutic potential in animal models of degenerative disease like Huntington’s and Parkinson’s disease in the central nervous system, which can be further investigated in the treatment of peripheral neurodegenerative diseases.^76–78 Several substances that have been proven to promote PGC1α expressions in human skeletal muscle, such as mitoquinone (mitoQ) and pyrroloquinoline quinone, were recommended to test their clinical potential in the treatment of peripheral neuropathy.^79,80 Other substances including hydrogen gas and inorganic nitrate targeting the PGC1α pathway to promote mitochondrial function are also tested in the prevention and treatment of CIPN.^81,82 Thus, modulation of the PGC1α-NRF1/2-TFAM axis in DRG neurons has the potential to promote mitochondrial regeneration or protect peripheral nerve fibers and prevent CIPN (Figure 1).

Other potential mitochondrial markers for CIPN diagnostics

To date, no specific biomarkers of mitochondrial dysfunction have been identified to determine the earliest changes or the severity of CIPN. There are indications that modulators of mitochondrial dysfunction may aid in CIPN diagnosis and predict the outcome of CIPN treatments. These modulators include 8-hydroxy-2’-deoxyguanosine (8-OHdG), mtDNA, and heat shock proteins (HSPs). 8-OHdG, the predominant production of free radical-induced oxidative lesions, has been widely used as a biomarker of oxidative stress and oxidative DNA damage in diseases.⁸³ Preclinical studies have shown that paclitaxel induces a rise of 8-OHdG in DRG and amplified oxidative stress to lead the neuropathic pain in rats.⁸⁴ These results suggested the potential diagnostic value of 8-OHdG as a biomarker in clinical trials.

Moreover, as transcription of mitochondrial genes and level of mitochondrial activity is often proportional to mtDNA copy number, circulating mtDNA has been wildly used as a biomarker for predicting mitochondrial dysfunction and diseases, including cardiovascular disease, metabolic diseases, and cancer.^85,86 Recently preclinical studies assessed the potential of circulating mtDNA as a blood biomarker to predict the progression of CIPN. Paclitaxel and bortezomib-induced increases in mtDNA levels were synchronized with the peak of pain behavioral manifestations. Especially, the mtDNA content (determined by mtDNA/nDNA ratio) in blood was increased in the early phase of oxaliplatin-induced CINP, before the emergence of pain-like behaviors. These results suggested that circulating mtDNA in the blood may use as a potential biomarker to identify early stages of CIPN. Furthermore, mtDNA copy number has often been used to evaluate the treatment of CIPN targeting mitochondrial dysfunction in the peripheral and central nervous system in preclinical research.^37,51 Together, these findings indicate that mtDNA may serve as a potential biomarker to predict and access the development stage of CIPN and its therapeutic effects.

In addition, several studies have also shown that HSP modulation is the underlying mechanism to prevent chemotherapy-induced neurotoxicity.^87–89 Recent findings have reported that human Hsp27 prevents mitochondrial dysfunction, neurotoxicity, and subsequent painful behavior induced by paclitaxel or vincristine.^90,91 These preclinical results suggest the potential of Hsp27 as a biomarker for the conservation of mitochondrial function and efficacy of CIPN treatment. However, studies on the conservation of mitochondrial function that refer to mitochondrial function are limited. Therefore, mechanism-based biomarkers, including PGC1α-modulators may potentially overcome this shortcoming. Taken together, these markers might be potential biomarkers in the clinical diagnosis for the stage and severity or efficacy of treatment in CIPN regarding mitochondrial dysfunction.

Conclusions and future perspective

In this review, we propose a scientific conclusion that PGC1α-mediated recovery of mitochondrial function might be a novel target for the treatment and prevention of CIPN. The ideas are clear and the theoretical basis is sufficient. As a transcriptional co-activator, PGC1α plays a key role in regulating oxidative stress and mitochondrial biosynthesis. Not limited to the traditional pain pathway, takes PGC1α as the target to study its mechanism of action in CIPN, which has important reference and guiding significance for elucidating the pathogenesis of CIPN, developing innovative drugs and clinical treatment for the prevention and treatment of CIPN. Therefore, targeting PGC1α is expected to be rapidly transformed and applied to fill the gap in the prevention and treatment of CIPN.

Regulation of PPARγ/PGC1α in sensory neurons activates mitochondrial transcription and achieves ‘purification and renewal’ of mitochondria. However, directly targeting PGC1α might cause severe side effects as PGC1α is majorly involved in non-shivering thermogenesis and temperature homeostasis in humans. Whereas indirectly regulating the expression level of PGC1α is an ideal means to interfere with mitochondrial regeneration. Besides, the upstream regulating and downstream responding signals of PGC1α-mediated mitochondrial regeneration also need to be further explored.

Last but not the least, several natural compounds and molecules targeting PGC1α, including resveratrol, evodiamine, berberine, and ghrelin have shown neuroprotective effects against CIPN and diabetic neuropathy in preclinical studies, further clinical trials refer to these molecules are highly recommended. The pathogenesis of CIPN discussed here is mainly derived from animal models of ‘pain induced by chemotherapy agents’ from preclinical studies. It does not fully represent the real situation of cancer patients treated with neurotoxic chemotherapy. Therefore, future clinical trials could also pave the way for the clinical translation of CIPN therapy targeting mitochondrial dysfunction.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Wuping Sun

References

Ferlay

Colombet

Soerjomataram

, et al. Cancer statistics for the year 2020: an overview. Int J Cancer. Epub ahead of print 5 April 2021. DOI: 10.1002/ijc.33588.

Dalakas

Semino-Mora

Leon-Monzon

. Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2’3’-dideoxycytidine (ddC). Lab Invest 2001; 81: 1537–1544.

Allemani

Matsuda

Di Carlo

, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018; 391: 1023–1075.

Siegel

Miller

Jemal

. Cancer statistics, 2020. CA Cancer J Clin 2020; 70: 7–30.

Guo

. Trends in cervical cancer mortality in China from1989 to 2018: an age-period study and joinpoint analysis. BMC Public Health 2021; 21: 1329.

Sisignano

Baron

Scholich

, et al. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol 2014; 10: 694–707.

Kao

Liao

Markovic

, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol 2017; 74: 1216–1222.

Staff

Grisold

, et al. Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol 2017; 81: 772–781.

Loprinzi

Lacchetti

Bleeker

, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol 2020; 38: 3325–3348.

10.

Terry

. Magnolia neurosciences launches with $31 million. Biospace, 13 August 2018, https://www.biospace.com/article/magnolia-neurosciences-launches-with-31-million/

11.

Trecarichi

Flatters

SJL

. Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced peripheral neuropathy. Int Rev Neurobiol 2019; 145: 83–126.

12.

Canta

Pozzi

Carozzi

. Mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy (CIPN). Toxics 2015; 3: 198–223.

13.

Areti

Yerra

Naidu

, et al. Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol 2014; 2: 289–295.

14.

Sahu

Langeh

Singh

, et al. Crosstalk between anticancer drugs and mitochondrial functions. Curr Res Pharmacol Drug Discov 2021; 2: 100047.

15.

Zajaczkowska

Kocot-Kepska

Leppert

, et al. Mechanisms of chemotherapy-induced peripheral neuropathy. Int J Mol Sci 2019; 20: 1451.

16.

Khuankaew

Sawaddiruk

Surinkaew

, et al. Possible roles of mitochondrial dysfunction in neuropathy. Int J Neurosci 2021; 131: 1019–1041.

17.

Fairchild

, et al. Painful diabetic peripheral neuropathy: role of oxidative stress and central sensitisation. Diabet Med 2022; 39: e14729.

18.

Dalakas

. Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst 2001; 6: 14–20.

19.

Lewis

Dalakas

. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1: 417–422.

20.

Doyle

Salvemini

. Mini-review: mitochondrial dysfunction and chemotherapy-induced neuropathic pain. Neurosci Lett 2021; 760: 136087.

21.

Flatters

SJL

Bennett

. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 2006; 122: 245–257.

22.

Sahenk

Barohn

New

, et al. Taxol neuropathy. Electrodiagnostic and sural nerve biopsy findings. Arch Neurol 1994; 51: 726–729.

23.

Fazio

Quattrini

Bolognesi

, et al. Docetaxel neuropathy: a distal axonopathy. Acta Neuropathol 1999; 98: 651–653.

24.

Xiao

Zheng

Bennett

. Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel. Neuroscience 2012; 203: 194–206.

25.

Zheng

Xiao

Bennett

. Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp Neurol 2012; 238: 225–234.

26.

Franco-Iborra

Vila

Perier

. Mitochondrial quality control in neurodegenerative diseases: focus on Parkinson’s disease and Huntington’s disease. Front Neurosci 2018; 12: 342.

27.

Garcia

Bartol

Phan

, et al. Mitochondrial morphology provides a mechanism for energy buffering at synapses. Sci Rep 2019; 9: 18306.

28.

Zheng

Xiao

Bennett

. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol 2011; 232: 154–161.

29.

Duggett

Griffiths

Flatters

SJL

. Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons. Pain 2017; 158: 1499–1508.

30.

Griffiths

Flatters

. Pharmacological modulation of the mitochondrial electron transport chain in paclitaxel-induced painful peripheral neuropathy. J Pain 2015; 16: 981–994.

31.

Podratz

Knight

, et al. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis 2011; 41: 661–668.

32.

Di Cesare Mannelli

Zanardelli

Failli

, et al. Oxaliplatin-induced neuropathy: oxidative stress as pathological mechanism. J Pain 2012; 13: 276–284.

33.

Shim

Bae

Wang

, et al. Peripheral and central oxidative stress in chemotherapy-induced neuropathic pain. Mol Pain 2019; 15: 1744806919840098.

34.

Fidanboylu

Griffiths

Flatters

. Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy. PLoS ONE 2011; 6: e25212.

35.

Popović

Klajn

Paunesku

, et al. Neuroprotective role of selected antioxidant agents in preventing cisplatin-induced damage of human neurons in vitro. Cell Mol Neurobiol 2019; 39: 619–636.

36.

Di Cesare Mannelli

Zanardelli

Landini

, et al. Effect of the SOD mimetic MnL4 on in vitro and in vivo oxaliplatin toxicity: possible aid in chemotherapy induced neuropathy. Free Radic Biol Med 2016; 93: 67–76.

37.

Gorgun

Zhuo

Englander

. Cisplatin toxicity in dorsal root ganglion neurons is relieved by meclizine via diminution of mitochondrial compromise and improved clearance of DNA damage. Mol Neurobiol 2017; 54: 7883–7895.

38.

Jobin

Butler

Overall

. New intracellular activities of matrix metalloproteinases shine in the moonlight. Biochim Biophys Acta Mol Cell Res 2017; 1864(Pt. A): 2043–2055.

39.

Tonello

Lee

Berta

. Monoclonal antibody targeting the matrix metalloproteinase 9 prevents and reverses paclitaxel-induced peripheral neuropathy in mice. J Pain 2019; 20: 515–527.

40.

Krukowski

Nijboer

Huo

, et al. Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor pifithrin-μ. Pain 2015; 156: 2184–2192.

41.

Maj

Krukowski

, et al. Inhibition of mitochondrial p53 accumulation by PFT-mu prevents cisplatin-induced peripheral neuropathy. Front Mol Neurosci 2017; 10: 108.

42.

Puigserver

Park

, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92: 829–839.

43.

McMeekin

Fox

Boas

, et al. Dysregulation of PGC-1alpha-dependent transcriptional programs in neurological and developmental disorders: therapeutic challenges and opportunities. Cells 2021; 10: 352.

44.

Rius-Perez

Torres-Cuevas

Millan

, et al. PGC-1alpha, inflammation, and oxidative stress: an integrative view in metabolism. Oxid Med Cell Longev 2020; 2020: 1452696.

45.

Esterbauer

Oberkofler

Krempler

, et al. Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. Genomics 1999; 62: 98–102.

46.

Sun

Uchida

Suzuki

, et al. Lack of TRPV2 impairs thermogenesis in mouse brown adipose tissue. EMBO Rep 2016; 17: 383–399.

47.

Chaturvedi

Adhihetty

Shukla

, et al. Impaired PGC-1alpha function in muscle in Huntington’s disease. Hum Mol Genet 2009; 18: 3048–3065.

48.

St-Pierre

Drori

Uldry

, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006; 127: 397–408.

49.

Puigserver

Spiegelman

. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 2003; 24: 78–90.

50.

Kang

Chu

Kaufman

. The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms. FEBS Lett 2018; 592: 793–811.

51.

Chen

, et al. β2-adrenoreceptor agonist ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of mitochondrial biogenesis. Biomed Pharmacother 2021; 144: 112331.

52.

Calcutt

Smith

Frizzi

, et al. Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy. J Clin Invest 2017; 127: 608–622.

53.

Fernyhough

. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. Curr Diab Rep 2015; 15: 89.

54.

Choi

Chandrasekaran

Inoue

, et al. PGC-1α regulation of mitochondrial degeneration in experimental diabetic neuropathy. Neurobiol Dis 2014; 64: 118–130.

55.

Zhang

Zhou

, et al. 5-HT1F receptor agonist ameliorates mechanical allodynia in neuropathic pain via induction of mitochondrial biogenesis and suppression of neuroinflammation. Front Pharmacol 2022; 13: 834570.

56.

Sun

Zhang

, et al. Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α -mediated mitochondrial biogenesis in the spinal cord. Oxid Med Cell Longev 2021; 2021: 9577874.

57.

Kim

Zhang

Gwak

, et al. Phenyl N-tert-butylnitrone, a free radical scavenger, reduces mechanical allodynia in chemotherapy-induced neuropathic pain in rats. Anesthesiology 2010; 112: 432–439.

58.

Duggett

Flatters

SJL

. Characterization of a rat model of bortezomib-induced painful neuropathy. Br J Pharmacol 2017; 174: 4812–4825.

59.

Toyama

Shimoyama

Ishida

, et al. Characterization of acute and chronic neuropathies induced by oxaliplatin in mice and differential effects of a novel mitochondria-targeted antioxidant on the neuropathies. Anesthesiology 2014; 120: 459–473.

60.

McCormick

Lowes

Colvin

, et al. MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model. Br J Anaesth 2016; 117: 659–666.

61.

Doyle

Chen

Muscoli

, et al. Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. J Neurosci 2012; 32: 6149–6160.

62.

Duggett

Griffiths

McKenna

, et al. Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy. Neuroscience 2016; 333: 13–26.

63.

Chen

. Evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammation and maintaining mitochondrial anti-oxidant functions. Hum Cell 2019; 32: 251–259.

64.

Yang

Wang

, et al. Resveratrol inhibits paclitaxel-induced neuropathic pain by the activation of PI3K/Akt and SIRT1/PGC1α pathway. J Pain Res 2019; 12: 879–890.

65.

Ishii

Tsubouchi

Miura

, et al. Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice. Eur J Pharmacol 2018; 819: 35–42.

66.

Hao

Gao

, et al. Translocator protein (TSPO) alleviates neuropathic pain by activating spinal autophagy and nuclear SIRT1/PGC-1α signaling in a Rat L5 SNL model. J Pain Res 2022; 15: 767–778.

67.

Bheereddy

Yerra

Kalvala

, et al. SIRT1 activation by polydatin alleviates oxidative damage and elevates mitochondrial biogenesis in experimental diabetic neuropathy. Cell Mol Neurobiol 2021; 41: 1563–1577.

68.

Chandrasekaran

Muragundla

Demarest

, et al. mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy. Ann Clin Transl Neurol 2017; 4: 844–858.

69.

Zhang

Song

Zhao

, et al. Quercetin attenuates diabetic peripheral neuropathy by correcting mitochondrial abnormality via activation of AMPK/PGC-1α pathway in vivo and in vitro. Front Neurosci 2021; 15: 636172.

70.

Yerra

Kalvala

Sherkhane

, et al. Adenosine monophosphate-activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in experimental diabetic neuropathy. Neuropharmacology 2018; 131: 256–270.

71.

Roy Chowdhury

Smith

Saleh

, et al. Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain 2012; 135(Pt. 6): 1751–1766.

72.

Zhang

Yang

, et al. Salvianolic acid A protects the peripheral nerve function in diabetic rats through regulation of the AMPK-PGC1alpha-Sirt3 axis. Molecules 2012; 17: 11216–11228.

73.

Hao

, et al. Antispasmodic drug drofenine as an inhibitor of Kv2.1 channel ameliorates peripheral neuropathy in diabetic mice. Iscience 2020; 23: 101617.

74.

Chandrasekaran

Anjaneyulu

Inoue

, et al. Mitochondrial transcription factor A regulation of mitochondrial degeneration in experimental diabetic neuropathy. Am J Physiol Endocrinol Metab 2015; 309: E132–E141.

75.

Chandrasekaran

Anjaneyulu

Choi

, et al. Role of mitochondria in diabetic peripheral neuropathy: influencing the NAD(+)-dependent SIRT1-PGC-1alpha-TFAM pathway. Int Rev Neurobiol 2019; 145: 177–209.

76.

Chandra

Sharma

Calingasan

, et al. Enhanced mitochondrial biogenesis ameliorates disease phenotype in a full-length mouse model of Huntington’s disease. Hum Mol Genet 2016; 25: 2269–2282.

77.

Anis

Zafeer

Firdaus

, et al. Ferulic acid reinstates mitochondrial dynamics through PGC1alpha expression modulation in 6-hydroxydopamine lesioned rats. Phytother Res 2020; 34: 214–226.

78.

Das

Vaidya

Khare

, et al. Combination of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist and PPAR gamma co-activator 1alpha (PGC-1alpha) activator ameliorates cognitive deficits, oxidative stress, and inflammation in rodent model of Parkinson’s disease. Curr Neurovasc Res 2021; 18: 497–507.

79.

Broome

Pham

Braakhuis

, et al. MitoQ supplementation augments acute exercise-induced increases in muscle PGC1alpha mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men. Redox Biol 2022; 53: 102341.

80.

Hwang

Machek

Cardaci

, et al. Effects of pyrroloquinoline quinone (PQQ) supplementation on aerobic exercise performance and indices of mitochondrial biogenesis in untrained men. J Am Coll Nutr 2020; 39: 547–556.

81.

Akagi

Baba

. Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Rep 2019; 41: 301–311.

82.

Roberts

Ashmore

McNally

, et al. Inorganic nitrate mimics exercise-stimulated muscular fiber-type switching and myokine and gamma-aminobutyric acid release. Diabetes 2017; 66: 674–688.

83.

Da˛browska

Wiczkowski

. Analytics of oxidative stress markers in the early diagnosis of oxygen DNA damage. Adv Clin Exp Med 2017; 26: 155–166.

84.

Miao

, et al. Nociceptive behavior induced by chemotherapeutic paclitaxel and beneficial role of antioxidative pathways. Physiol Res 2019; 68: 491–500.

85.

Malik

Czajka

. Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction. Mitochondrion 2013; 13: 481–492.

86.

Castellani

Longchamps

Sun

, et al. Thinking outside the nucleus: mitochondrial DNA copy number in health and disease. Mitochondrion 2020; 53: 214–223.

87.

Zhu

Carozzi

Reed

, et al. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity. Sci Rep 2016; 6: 28861.

88.

Zhu

Chen

, et al. Ethoxyquin prevents chemotherapy-induced neurotoxicity via Hsp90 modulation. Ann Neurol 2013; 74: 893–904.

89.

Cetinkaya-Fisgin

Zhu

Luan

, et al. Development of EQ-6, a novel analogue of ethoxyquin to prevent chemotherapy-induced peripheral neuropathy. Neurotherapeutics 2021; 18: 2061–2072.

90.

Chine

NPB

Kumar

, et al. Targeting axon integrity to prevent chemotherapy-induced peripheral neuropathy. Mol Neurobiol 2019; 56: 3244–3259.

91.

Chine

NPB

CHE

. Therapeutic benefits of maintaining mitochondrial integrity and calcium homeostasis by forced expression of Hsp27 in chemotherapy-induced peripheral neuropathy. Neurobiol Dis 2019; 130: 104492.