Clavulanic Acid Attenuating Effect on the Diabetic Neuropathic Pain in Rats

Diabetic neuropathy is one of the most common complications of diabetes mellitus. Excess glutamate release and oxidative stress are hypothesized to be involved in the pathophysiology of diabetes-induced neuropathy. This study was designed to investigate the effect of clavulanic acid (CLAV), a compet...

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Bibliographic Details
Published in:	Neurochemical research Vol. 46; no. 7; pp. 1759 - 1770
Main Authors:	Kolahdouz, Mahnoush, Jafari, Faranak, Falanji, Farahnaz, Nazemi, Samad, Mohammadzadeh, Mohammad, Molavi, Mehdi, Amin, Bahareh
Format:	Journal Article
Language:	English
Published:	New York Springer US 01-07-2021 Springer Nature B.V
Subjects:	Analgesics - therapeutic use Animal models Animals Apoptosis Behavior, Animal - drug effects Biochemistry Biomedical and Life Sciences Biomedicine Cell Biology Clavulanic acid Clavulanic Acid - therapeutic use Complications Cytokines Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - chemically induced Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - metabolism Diabetic Neuropathies - drug therapy Diabetic Neuropathies - etiology Diabetic Neuropathies - metabolism Diabetic neuropathy Gene Expression - drug effects Genes Hyperalgesia Hyperalgesia - drug therapy Hyperalgesia - etiology Hyperalgesia - metabolism Inflammation Male Neuralgia - drug therapy Neuralgia - etiology Neuralgia - metabolism Neurochemistry Neurology Neurosciences Nitric oxide Nitric-oxide synthase Open Field Test - drug effects Original Paper Oxidative stress Pain Pain perception Rats Rats, Wistar Spinal cord Spinal Cord - drug effects Spinal Cord - metabolism Streptozocin Tumor necrosis factor-TNF Tumor necrosis factor-α β Lactamase iNOS GLT1 TNF-α Diabetic neuropathic pain Clavulanic acid Apoptosis
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Summary:	Diabetic neuropathy is one of the most common complications of diabetes mellitus. Excess glutamate release and oxidative stress are hypothesized to be involved in the pathophysiology of diabetes-induced neuropathy. This study was designed to investigate the effect of clavulanic acid (CLAV), a competitive beta-lactamase inhibitor, on the streptozocin (STZ)-induced neuropathic pain and possible mechanisms in the spinal cord of rats. Male Wistar rats were divided into naive group; control group which got a single dose of STZ (50 mg/kg, i.p.), as a model of diabetic neuropathic pain; prophylactic groups: animals received CLAV (10, 20 and 40 mg/kg, i.p.) 1 week after STZ for 10 days; and therapeutic group: animals received 20 mg/kg CLAV, 21 days after STZ for 10 days. Study of pain behaviors was started on days 0, 7, 14, 21, 28, 35 and 42 after STZ. The expression of the glutamate transport 1 (GLT1), genes of oxidative stress including inducible nitric oxide synthase (iNOS), proinflammatory cytokine, tumor necrosis factor alpha (TNF-α), as well as genes involved in the apoptosis including bcl2, bcl2-associated x (bax) were measured in the spinal cord tissue by Real Time PCR, on day 42. On day 21 post injection of STZ, diabetic animals showed significant mechanical allodynia, cold allodynia and thermal hyperalgesia. CLAV in all doses of 10, 20 and 40 mg/kg reduced symptoms of allodynia and hyperalgesia, in both prophylactic and therapeutic regimens. While iNOS, TNF-α, bax/bcl2 were found significantly overexpressed in spinal cord of diabetic animals, their expression in animals received CLAV had been reduced. In contrast, GLT1 that had decreased in the spinal cord of diabetic animals, significantly increased in those received CLAV. CLAV was found a promising candidate for reliving neuropathic pain in diabetes mellitus. Such beneficial effect of CLAV could be, in part, attributed to the increased expression of GLT 1, inhibition of nitrosative stress, anti-inflammation, and inhibition of some apoptotic mediators followed by administration into diabetic animals.
ISSN:	0364-3190 1573-6903
DOI:	10.1007/s11064-021-03308-y