Effect of cilostazol on experimental diabetic neuropathy in the rat

Kihara, Mikihiro; Schmelzer, James D.; Low, Phillip A.

doi:10.1007/bf00400579

Cited by 37 publications

(7 citation statements)

References 20 publications

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“…Apart from its positive effects on vascular and endothelial abnormalities, information on the benefits of cilostazol on peripheral nerve function remains limited. The action of cilostazol on the peripheral nerve includes increased nerve blood flow and restoration of nerve Na⁺/K⁺-ATPase activity, leading to improved sciatic-tibial nerve conduction velocity and amelioration of DPN ( Kihara et al, 1995 ; Naka 1995 ). In addition, the neuroprotective effects of cilostazol include the ability to promote axonal regeneration in the sciatic nerves of DM rats ( Yamamoto et al, 1998 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Background: Cilostazol is an antiplatelet agent with vasodilating, endothelial function restoration, and anti-inflammatory effects. This study aims to investigate the efficacy of oral cilostazol for preventing the development of diabetic peripheral neuropathy (DPN).Materials and Methods: Ninety adult male Sprague-Dawley rats were divided into five groups: 1) naïve (control); 2) diabetic (DM); 3) DM receiving 10 mg/kg cilostazol (cilo-10); 4) DM receiving 30 mg/kg cilostazol (cilo-30); and 5) DM receiving 100 mg/kg cilostazol (cilo-100). Hindpaw responses to thermal and mechanical stimuli were measured. Activation of microglia and astrocytes in the spinal dorsal horn (SDH) and expression of NaVs in the dorsal root ganglia (DRG) were examined with Western blots and immunofluorescence.Results: DM rats displayed decreased withdrawal thresholds to mechanical stimuli (mechanical allodynia) and blunted responses to thermal stimuli. In addition, the expression of microglia increased, but astrocytes were reduced in the SDH. Upregulation of Nav −1.1, 1.2, −1.3, −1.6, and −1.7 and downregulation of Nav-1.8 were observed in the DRG. The DM rats receiving cilostazol all returned DM-induced decrease in withdrawal threshold to mechanical stimuli and attenuated neuropathic pain. Additionally, all cilostazol treatments suppressed the level of activated microglial cells and ameliorated the DM-induced decline in astrocyte expression levels in the SDH. However, only the rats treated with cilo-100 demonstrated significant improvements to the aberrant NaV expression in the DRG.Conclusion: Oral cilostazol can blunt the responses of mechanical allodynia and has the potential to treat diabetic neuropathy by attenuating NaV and glial cell dysregulation.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…Opioid analgesics are considered alternative or supplemental therapeutic medicines [39]. However, cilostazol, a speci c cAMP phosphodiesterase inhibitor, has been shown to improve motor function in diabetic rats by ameliorating motor nerve conduction velocity, restoring nerve Na + /K + -ATPase activity, and improving mean myelinated ber thickness and axonal atrophic changes in peripheral nerves [17,19,40]. Furthermore, cilostazol increased ornithine decarboxylase activity in the dorsal root ganglion, and the axonal regeneration rate in the sciatic nerves of DM rats has also been reported [41].…”

Section: Discussionmentioning

confidence: 99%

“…Diverse results of cilostazol in DN treatment show bene cial effects through the improvement of Na + /K + -ATPase activity by directly increasing cAMP and NO production in the human neuroblastoma cell line SH-SY5Y [16]. Furthermore, in experimental animal models of DN, a cilostazol-supplemented diet improved both nerve blood ow and nerve conduction [17]. Evidence from our previous diabetic animal experiment suggests that cilostazol can blunt the responses to mechanical allodynia and has the potential to treat DN by attenuating sodium channels and glial cell dysregulation [18].…”

Section: Introductionmentioning

confidence: 99%

Cilostazol ameliorates motor dysfunction and Schwann cell impairment in streptozotocin-induced diabetic rats

Chang

Wang

et al. 2023

Preprint

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This study investigated the effects of cilostazol on motor dysfunction, spinal motor neuron abnormalities, and schwannopathy in rats with diabetes. Diabetes mellitus (DM) was induced in rats via femoral intravenous streptozotocin (STZ) injection (60 mg/kg). After successful DM induction, cilostazol was administered on day 15 via oral gavage (100 mg/kg/day) for 6 weeks until sacrifice. Behavioral assays, including motor function were performed weekly. The sciatic nerve, L5 spinal cord, and spinal ventral root were collected to evaluate the expression of the glial fibrillary acidic protein (GFAP), myelin protein zero (P0), and choline acetyltransferase (ChAT) by immunofluorescence and Western blotting. DM rats displayed decreased running speeds, running distance, and toe spread but increased foot pressure. In addition, loss of non-myelinating Schwann cells and myelin sheaths was observed in the sciatic nerve and L5 spinal ventral root. Reduced numbers of motor neurons were also found in the L5 spinal ventral horn. Cilostazol administration significantly potentiated running speed and distance, increased hind paw toe spread, and decreased foot pressure. In the sciatic nerve and L5 spinal ventral root, cilostazol treatment significantly improved non-myelinated Schwann cells and increased myelin mass. ChAT expression in motor neurons in the spinal ventral horn was improved, but not significantly. Cilostazol administration may protect sensorimotor function in diabetic rats.

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“…However, accumulating evidence suggests that vasodilators can prevent the progression of DPN, including neural dysfunction, nerve degeneration, and hyposensitivity. 15 – 19 Thus, these effects are likely to be caused by amelioration of the diabetic vascular impairment, but probably not through inhibition of TRPA1 sensitization/activation.…”

Section: Discussionmentioning

confidence: 99%

“… 14 Furthermore, in experimental diabetic animal models, a variety of vasodilator agents ameliorate vascular impairment, neural dysfunction, nerve degeneration, loss of sensitivity, and neuropathic pain. 15 – 19 …”

Section: Introductionmentioning

confidence: 99%

TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy

Hiyama

Yano

et al. 2018

Mol Pain

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BackgroundDiabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice.ResultsStreptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration.ConclusionThese results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.

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Effect of cilostazol on experimental diabetic neuropathy in the rat

Cited by 37 publications

References 20 publications

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

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

Cilostazol ameliorates motor dysfunction and Schwann cell impairment in streptozotocin-induced diabetic rats

TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy

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