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Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice.

ABSTRACT: Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16INK4A and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological 'senolytic' agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN.

SUBMITTER: Acklin S

PROVIDER: S-EPMC7447787 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice.

Acklin Scarlett S Zhang Manchao M Du Wuying W Zhao Xin X Plotkin Matthew M Chang Jianhui J Campisi Judith J Zhou Daohong D Xia Fen F

Scientific reports 20200825 1

Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse ...[more]

PMID: 32843706

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Project description:BackgroundThe main symptoms of chemotherapy-induced peripheral neuropathy (CIPN) include pain and numbness. Neuronal G protein-coupled receptor kinase 2 (GRK2) plays an important role in various pain models. Cisplatin treatment can induce the activation of proinflammatory microglia in spinal cord. The purpose of this study was to investigate the role of spinal neuronal GRK2 in cisplatin-induced CIPN and in the prevention of CIPN by electroacupuncture (EA).MethodsThe pain and sensory deficit behaviors of mice were examined by von Frey test and adhesive removal test. The expression of neuronal GRK2 in the spinal cord is regulated by intraspinal injection of adeno-associated virus (AAV) containing neuron-specific promoters. The protein levels of GRK2, triggering receptor expressed on myeloid cells 2 (TREM2), and DNAX-activating protein of 12 kDa (DAP12) in spinal dorsal horn were detected by Western blot, the density of intraepidermal nerve fibers (IENFs) was detected by immunofluorescence, and microglia activation were evaluated by real-time polymerase chain reaction (PCR).ResultsIn this study, cisplatin treatment led to the decrease of GRK2 expression in the dorsal horn of spinal cord. Overexpression of neuronal GRK2 in spinal cord by intraspinal injection of an AAV vector expressing GRK2 with human synapsin (hSyn) promotor significantly inhibited the loss of IENFs and alleviated the mechanical pain and sensory deficits induced by cisplatin. Real-time PCR analysis showed that the overexpression of neuronal GRK2 significantly inhibited the messenger RNA (mRNA) upregulation of proinflammatory cytokine interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS), and M1 microglia marker cluster of differentiation (CD)16 induced by cisplatin. Furthermore, the TREM2 and DAP12, which has been demonstrated to play a role in microglia activation and in the development of CIPN, were also downregulated by overexpression of neuronal GRK2 in this study. Interestingly, preventive treatment with EA completely mimics the effect of overexpression of neuronal GRK2 in the spinal cord in this mouse model of cisplatin-induced CIPN. EA increased GRK2 level in spinal dorsal horn after cisplatin treatment. Intraspinal injection of AAV vector specifically downregulated neuronal GRK2, completely reversed the regulatory effect of EA on CIPN and microglia activation. All these indicated that the neuronal GRK2 mediated microglial activation contributed to the process of CIPN.ConclusionsNeuronal GRK2 in the spinal cord contributed to the preventive effect of EA on CIPN. The neuronal GRK2 may be a potential target for CIPN intervention.

Project description:Chemotherapy-induced peripheral neuropathy (CIPN), a debilitating major side effect of cancer treatment, is characterized by pain and sensory loss in hand and feet. Platinum-based chemotherapeutics like cisplatin frequently induce CIPN. The molecular mechanism underlying these neurotoxic symptoms is incompletely understood and there are no preventive or curative interventions. We hypothesized that cisplatin acts as a cellular stressor that triggers p53 accumulation at mitochondria, leading to mitochondrial dysfunction and CIPN. To test this hypothesis, we examined the effect of the small molecule pifithrin-μ (PFT-μ), an inhibitor of p53 mitochondrial association on CIPN and the associated mitochondrial dysfunction. We show here for the first time that in vivo cisplatin rapidly increases mitochondrial accumulation of p53 in dorsal root ganglia (DRG), spinal cord, and peripheral nerve without evidence for apoptosis. Cisplatin-treatment also reduced mitochondrial membrane potential and lead to abnormal mitochondrial morphology and impaired mitochondrial function in DRG neurons. Pre-treatment with PFT-μ prevented the early cisplatin-induced increase in mitochondrial p53 and the reduction in mitochondrial membrane potential. Inhibition of the early mitochondrial p53 accumulation by PFT-μ also prevented the abnormalities in mitochondrial morphology and mitochondrial bioenergetics (reduced oxygen consumption rate, maximum respiratory capacity, and adenosine triphosphate synthesis) that develop in DRG and peripheral nerve after cisplatin-treatment. Functionally, inhibition of mitochondrial p53 accumulation prevented the hallmarks of CIPN including mechanical allodynia, peripheral sensory loss (numbness) as quantified by an adhesive-removal task, and loss of intra-epidermal nerve fibers. In conclusion, PFT-μ is a potential neuroprotective agent that prevents cisplatin-induced mitochondrial dysfunction in DRG and peripheral nerves thereby protecting against CIPN through blockade of the early cisplatin-induced increase in mitochondrial p53. Notably, there is accumulating evidence that PFT-μ has anti-tumor activities and could therefore be an attractive candidate to prevent CIPN while promoting tumor cell death.

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Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice.

Publications

Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice.

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