Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN

2021 ◽  
Vol 221 (2) ◽  
Author(s):  
Yihang Li ◽  
Maria F. Pazyra-Murphy ◽  
Daina Avizonis ◽  
Mariana de Sá Tavares Russo ◽  
Sophia Tang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Sensory Neurons ◽  
Calcium Flux ◽  
Axon Degeneration ◽  
Critical Event ◽  
Calcium Stores ◽  
Nerve Terminals ◽  
Calcium Dysregulation ◽  
Dying Back

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a “dying-back” axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN).

scholarly journals Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN

2021 ◽  
Author(s):  
Yihang Li ◽  
Maria F. Pazyra-Murphy ◽  
Daina Avizonis ◽  
Mariana de Sa Tavares Russo ◽  
Sophia Tang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Calcium Flux ◽  
Axon Degeneration ◽  
Critical Event ◽  
Calcium Stores ◽  
List Type ◽  
Calcium Dysregulation ◽  
Dying Back

SUMMARYCancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a “dying-back” axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating CIPN.HIGHLIGHTSPaclitaxel induces intra-axonal calcium fluxSarm1-dependent cADPR production promotes axonal calcium elevation and degenerationAntagonizing cADPR signaling pathway protects against paclitaxel-induced peripheral neuropathy in vitro and in vivo

scholarly journals Exploring the relationship among dispositional optimism, health-related quality of life, and CIPN severity among colorectal cancer patients with chronic peripheral neuropathy

2021 ◽  
Author(s):  
Hester.R. Trompetter ◽  
Cynthia S. Bonhof ◽  
Lonneke V. van de Poll-Franse ◽  
Gerard Vreugdenhil ◽  
Floortje Mols
Keyword(s):  
Quality Of Life ◽  
Colorectal Cancer ◽  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Anxiety Symptoms ◽  
Health Related Quality ◽  
Related Quality ◽  
Health Related

Abstract Purpose Chemotherapy-induced peripheral neuropathy ((CI)PN) becomes chronic in 30% of cancer patients. Knowledge of predictors of chronic (CI)PN and related impairments in health-related quality of life (HRQoL) is lacking. We examined the role of optimism in chronic (CI)PN severity and associated HRQoL in colorectal cancer (CRC) patients up to two years after diagnosis. Methods CRC patients from a prospective cohort study participated, with sensory peripheral neuropathy (SPN) 1 year after diagnosis (n = 142). Multivariable regression analyses examined the cross-sectional association between optimism (measured by the LOT-R) and SPN severity/HRQoL (measured by the EORTC QLQ-CIPN20 and QLQ-C30), as well as the prospective association in a subsample that completed measures 2 years after diagnosis and still experienced SPN (n = 86). Results At 1-year follow-up, higher optimism was associated with better global HRQoL, and better physical, role, emotional, cognitive, and social functioning (all p < .01). Optimism at year one was also prospectively associated with better global HRQoL (p < .05), and emotional and cognitive functioning at 2-year follow-up (both p < .01). Optimism was not related to self-reported SPN severity. Significant associations were retained when controlling for demographic/clinical variables, and became non-significant after controlling for depressive and anxiety symptoms. Conclusions Optimism and depressive and anxiety symptoms are associated with HRQoL in CRC patients with chronic (CI)PN. Future research may illuminate the mechanisms that these factors share, like the use of (non)adaptive coping styles such as avoidance and acceptance that may inform the design of targeted interventions to help patients to adapt to chronic (CI)PN.

Chemotherapy-induced peripheral neuropathy in gynecologic cancer patients: risk factors and functional impact

2018 ◽  
Vol 19 (3) ◽  
pp. S101-S102
Author(s):  
H. Bulls ◽  
A. Hoogland ◽  
N. Chahal ◽  
B. Small ◽  
B. Gonzalez ◽  
...  
Keyword(s):  
Risk Factors ◽  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Gynecologic Cancer ◽  
Functional Impact

scholarly journals Treatment strategies for chemotherapy-induced peripheral neuropathy: potential role of exercise

2011 ◽  
Vol 4 (2) ◽  
pp. 117
Author(s):  
Karen Y. Wonders ◽  
Beverly S. Reigle ◽  
Daniel G. Drury
Keyword(s):  
Quality Of Life ◽  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Lifestyle Modification ◽  
Treatment Strategies ◽  
Moderate Intensity ◽  
Moderate Intensity Exercise ◽  
Exercise Rehabilitation

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting effect of cancer therapy that often has negative implications on a patient’s quality of life. The pain associated with CIPN has long been recognized as one of the most difficult types of pain to treat. Historically, much effort has been made to explore pharmacological therapies aimed at reducing symptoms of CIPN. While many of these agents provide a modest relief in the symptoms of peripheral neuropathy, many have been shown to have additional negative side effects for cancer patients. Therefore, the authors suggest exercise rehabilitation as one lifestyle modification that may positively impact the lives of patients with CIPN. To our knowledge, there are currently no published clinical trials examining the role of exercise in preserving neurological function following chemotherapy. However, investigations using low-to-moderate intensity exercise as an intervention in patients with diabetic peripheral neuropathy and hereditary motor and sensory neuropathies have produced promising results. Given that cancer patients appear to tolerate exercise, it seems plausible that exercise rehabilitation could be used as an effective strategy to minimize CIPN-induced detriments to quality of life.

scholarly journals Utility of screening tool for assessment of chemotherapy induced peripheral neuropathy in cancer patients

2019 ◽  
Vol 30 ◽  
pp. ix148
Author(s):  
P.R. Paibhavi ◽  
M.K. Muddiguba ◽  
V.V. Maka ◽  
A. Mandepudi ◽  
S.P. Kanneganti
Keyword(s):  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Screening Tool

scholarly journals Sensory Neurons, Ion Channels, Inflammation and the Onset of Neuropathic Pain

2012 ◽  
Vol 39 (4) ◽  
pp. 416-435 ◽  
Author(s):  
Patrick L. Stemkowski ◽  
Peter A. Smith
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Pain Management ◽  
Sensory Neurons ◽  
Inflammatory Mediators ◽  
Primary Afferents ◽  
Ectopic Activity ◽  
Management Procedures

Neuropathic pain often fails to respond to conventional pain management procedures. here we review the aetiology of neuropathic pain as would result from peripheral neuropathy or injury. We show that inflammatory mediators released from damaged nerves and tissue are responsible for triggering ectopic activity in primary afferents and that this, in turn, provokes increased spinal cord activity and the development of ‘central sensitization’. Although evidence is mounting to support the role of interleukin-1β, prostaglandins and other cytokines in the onset of neuropathic pain, the clinical efficacy of drugs which antagonize or prevent the actions of these mediators is yet to be determined. basic science findings do, however, support the use of pre-emptive analgesia during procedures which involve nerve manipulation and the use of anti-inflammatory steroids as soon as possible following traumatic nerve injury.

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