Cilostazol Ameliorates Peripheral Neuropathic Pain in Streptozotocin-Induced Type I Diabetic Rats

Cheng, Kuang‐I; Wang, Hung-Chen; Tseng, Kuang‐Yi; Wang, Yi‐Hsuan; Chang, Chih-Yuan; Chen, Yijing; Lai, Chung-Sheng; Chen, Dar‐Ren; Chang, Lin‐Li

doi:10.3389/fphar.2021.771271

Cited by 12 publications

(13 citation statements)

References 49 publications

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“…Blood glucose levels were assessed via the tail vein using an Accu-Chek ® Performa blood glucose assay kit. This femoral vein STZ injection model has a 100% success rate in producing type I DM rats, as indicated by the rapid development of hyperglycemia within 3 days of operation, with a less than 5% mortality rate so far [ 20 ]. The choices of cilostazol dosages for this experiment were based on previous publications by Naka et al (1995) for the lower 10 and 30 mg/kg dosages [ 18 ], and Rosales et al (2011) for the high dose [ 12 ].…”

Section: Methodsmentioning

confidence: 99%

Peripheral Nerve Denervation in Streptozotocin-Induced Diabetic Rats Is Reduced by Cilostazol

Tseng

Wang

et al. 2023

Medicina

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Background and Objective: Our previous study demonstrated that consistent treatment of oral cilostazol was effective in reducing levels of painful peripheral neuropathy in streptozotocin-induced type I diabetic rats. As diabetic neuropathy is characterized by hyperglycemia-induced nerve damage in the periphery, this study aims to examine the neuropathology as well as the effects of cilostazol treatments on the integrity of peripheral small nerve fibers in type I diabetic rats. Materials and Methods: A total of ninety adult male Sprague-Dawley rats were divided into the following groups: (1) naïve (control) group; (2) diabetic rats (DM) group for 8 weeks; DM rats receiving either (3) 10 mg/kg oral cilostazol (Cilo10), (4) 30 mg/kg oral cilostazol (Cilo30), or (5) 100 mg/kg oral cilostazol (Cilo100) for 6 weeks. Pain tolerance thresholds of hind paws toward thermal and mechanical stimuli were assessed. Expressions of PGP9.5, P2X3, CGRP, and TRPV-1 targeting afferent nerve fibers in hind paw skin and glial cells in the spinal dorsal horn were examined via immunohistochemistry and immunofluorescence. Results: Oral cilostazol ameliorated the symptoms of mechanical allodynia but not thermal analgesia in DM rats. Significant reductions in PGP9.5-, P2X3-, CGRP, and TRPV-1-labeled penetrating nerve fibers in the epidermal layer indicated denervation of sensory nerves in the hind paw epidermis of DM rats. Denervation significantly improved in groups that received Cilo30 and Cilo100 in a dose-dependent manner. Cilostazol administration also suppressed microglial hyperactivation and increased astrocyte expressions in spinal dorsal horns. Conclusions: Oral cilostazol ameliorated hyperglycemia-induced peripheral small nerve fiber damage in the periphery of diabetic rats and effectively mitigated diabetic neuropathic pain via a central sensitization mechanism. Our findings present cilostazol not only as an effective option for managing symptoms of neuropathy but also for deterring the development of diabetic neuropathy in the early phase of type I diabetes.

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Section: Methodsmentioning

confidence: 99%

Peripheral Nerve Denervation in Streptozotocin-Induced Diabetic Rats Is Reduced by Cilostazol

Tseng

Wang

et al. 2023

Medicina

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“…Nav.16 is upregulated in diabetic peripheral neuropathy rats. 116 Nav1.6 activation in skin and gut leads to increased response to mechanical stimuli and mechanical allodynia but not thermal allodynia. 117 The roles of Nav1.3 and Nav 1.6 in human chronic pain have not been determined.…”

Section: Cytokine Microenvironment Hypothesis Of Chronic Painmentioning

confidence: 97%

“… 138 Nav1.6 Involved in diabetic NP. 116 , 117 Not determined. Up- and downregulated by TNF-α and IL-10.…”

Section: Cytokine Microenvironment Hypothesis Of Chronic Painmentioning

confidence: 99%

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Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

Liu¹

2022

JIR

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Chronic pain, which affects around 1/3 of the world population and is often comorbid with memory deficit and mood depression, is a leading source of suffering and disability. Studies in past decades have shown that hyperexcitability of primary sensory neurons resulting from abnormal expression of ion channels and central sensitization mediated pathological synaptic plasticity, such as long-term potentiation in spinal dorsal horn, underlie the persistent pain. The memory/emotional deficits are associated with impaired synaptic connectivity in hippocampus. Dysregulation of numerous endogenous proteins including receptors and intracellular signaling molecules is involved in the pathological processes. However, increasing knowledge contributes little to clinical treatment. Emerging evidence has demonstrated that the neuroinflammation, characterized by overproduction of pro-inflammatory cytokines and glial activation, is reliably detected in humans and animals with chronic pain, and is sufficient to induce persistent pain and memory/emotional deficits. The abnormal expression of ion channels and pathological synaptic plasticity in spinal dorsal horn and in hippocampus are resulting from neuroinflammation. The neuroinflammation is initiated and maintained by the interactions of circulating monocytes, glial cells and neurons. Obviously, unlike infectious diseases and cancer, which are caused by pathogens or malignant cells, chronic pain is resulting from alterations of cells and molecules which have numerous physiological functions. Therefore, normalization (counterbalance) but not simple inhibition of the neuroinflammation is the right strategy for treating neuronal disorders. Currently, no such agent is available in clinic. While experimental studies have demonstrated that intracellular Mg 2+ deficiency is a common feature of chronic pain in animal models and supplement Mg 2+ are capable of normalizing the neuroinflammation, activation of upregulated proteins that promote recovery, such as translocator protein (18k Da) or liver X receptors, has a similar effect. In this article, relevant experimental and clinical evidence is reviewed and discussed.

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“…Although, the identity of the specific Na V isoforms modulated by capsaicin remain to be explored. Another approach targetting Na V channels in DSN is the use of the antithrombotic agent cilostazol ( Cheng et al, 2022 ). The interest on cilostazol for DSN symptoms stems from its known protection of human endothelial cells via activation of ERK1/2 and p38 MAPKs (MAPK) ( Lim et al, 2009 ), and neuroprotection in animal models of cerebral ischemia ( Iwama et al, 2007 ).…”

Section: The Therapeutic Potential Of Na V Cha...mentioning

confidence: 99%

Voltage-gated sodium channels in diabetic sensory neuropathy: Function, modulation, and therapeutic potential

Bigsby

Neapetung

Campanucci

2022

Front. Cell. Neurosci.

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Voltage-gated sodium channels (NaV) are the main contributors to action potential generation and essential players in establishing neuronal excitability. NaV channels have been widely studied in pain pathologies, including those that develop during diabetes. Diabetic sensory neuropathy (DSN) is one of the most common complications of the disease. DSN is the result of sensory nerve damage by the hyperglycemic state, resulting in a number of debilitating symptoms that have a significant negative impact in the quality of life of diabetic patients. Among those symptoms are tingling and numbness of hands and feet, as well as exacerbated pain responses to noxious and non-noxious stimuli. DSN is also a major contributor to the development of diabetic foot, which may lead to lower limb amputations in long-term diabetic patients. Unfortunately, current treatments fail to reverse or successfully manage DSN. In the current review we provide an updated report on NaV channels including structure/function and contribution to DSN. Furthermore, we summarize current research on the therapeutic potential of targeting NaV channels in pain pathologies, including DSN.

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Cilostazol Ameliorates Peripheral Neuropathic Pain in Streptozotocin-Induced Type I Diabetic Rats

Cited by 12 publications

References 49 publications

Peripheral Nerve Denervation in Streptozotocin-Induced Diabetic Rats Is Reduced by Cilostazol

Peripheral Nerve Denervation in Streptozotocin-Induced Diabetic Rats Is Reduced by Cilostazol

Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

Voltage-gated sodium channels in diabetic sensory neuropathy: Function, modulation, and therapeutic potential

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