Streptozotocin-induced diabetic hyperalgesia in rats is associated with upregulation of toll-like receptor 4 expression

Yan, Jian-e; Yuan, Wei; Lou, Xiaoli; Zhu, Tao

doi:10.1016/j.neulet.2012.08.012

Cited by 39 publications

(28 citation statements)

References 28 publications

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“…Interestingly 3a-diol, but not DHT, counteracted the increase induced by diabetes in the expression of TLR4. This may contribute to the analgesic action of 3a-diol, since the activation and upregulation of TLR4 is correlated with neuropathic pain (Yan et al 2012, Wei et al 2013.…”

Section: Discussionmentioning

confidence: 99%

Diabetic neuropathic pain: a role for testosterone metabolites

Calabrese¹,

Giatti²,

Romano³

et al. 2014

Journal of Endocrinology

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Diabetic neuropathy is associated with neuropathic pain in about 50% of diabetic subjects. Clinical management of neuropathic pain is complex and so far unsatisfactory. In this study, we analyzed the effects of the testosterone metabolites, dihydrotestosterone (DHT), and 3a-diol, on nociceptive and allodynia thresholds and on molecular and functional parameters related to pain modulation in the dorsal horns of the spinal cord and in the dorsal root ganglia of rats rendered diabetic by streptozotocin injection. Furthermore, the levels of DHT and 3a-diol were analyzed in the spinal cord. Diabetes resulted in a significant decrease in DHT levels in the spinal cord that was reverted by DHT or 3a-diol treatments. In addition, 3a-diol treatment resulted in a significant increase in 3a-diol in the spinal cord compared with control values. Both steroids showed analgesic properties on diabetic neuropathic pain, affecting different pain parameters and possibly by different mechanisms of action. Indeed, DHT counteracted the effect of diabetes on the mechanical nociceptive threshold, pre-and post-synaptic components, glutamate release, astrocyte immunoreactivity, and expression of interleukin-1b (IL1b), while 3a-diol was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity and the expression of substance P, toll-like receptor 4, tumor necrosis factor-a, transforming growth factor b-1, IL1b, and translocator protein. These results indicate that testosterone metabolites are potential agents for the treatment of diabetic neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Diabetic neuropathic pain: a role for testosterone metabolites

Calabrese¹,

Giatti²,

Romano³

et al. 2014

Journal of Endocrinology

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“…Treatments were started 4 weeks after the induction of diabetes to permit the development of peripheral neuropathy in diabetic rats .…”

Section: Methodsmentioning

confidence: 99%

“…Treatments were started 4 weeks after the induction of diabetes to permit the development of peripheral neuropathy in diabetic rats [5,16]. Blood glucose level monitoring Fasting blood glucose measurement Fasting blood glucose levels of the animals were measured weekly in the tail vein blood, using the Glukotrend â device (Roche).…”

Section: Induction Of Experimental Diabetesmentioning

confidence: 99%

Effect of subacute agomelatine treatment on painful diabetic neuropathy: involvement of catecholaminergic mechanisms

Aydin

Can

Özkay

et al. 2016

Fundamemntal Clinical Pharma

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In this study, we investigated the effects of subacute agomelatine (40 and 80 mg/kg) administration on chronic hyperglycemia, metabolic parameters, and pain perception in streptozotocin-induced diabetic rats. Fasting blood glucose measurements and oral glucose tolerance tests were performed to evaluate the effect of agomelatine on glycemia, while metabolic parameters were monitored using metabolic cages. Potential effect of agomelatine on diabetes-induced mechanical and thermal allodynia was evaluated using dynamic plantar aesthesiometer and warm plate (38 °C) tests, respectively. Additionally, influence of agomelatine on hyperalgesia occurring in connection with diabetic neuropathy was examined using the Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold plate (4 °C, thermal nociceptive stimulus) tests. Obtained data indicated that, in diabetic rats, agomelatine significantly improved hyperalgesia and allodynia responses, without no effect on hyperglycemia or the associated polydipsia, polyuria, and hyperphagia. Therapeutic potential of agomelatine on neuropathic pain was suppressed with α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis), phentolamine (a nonselective α-adrenoceptor antagonist), and propranolol (a nonselective β-adrenoceptor antagonist) administrations. However, p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis) pretreatment could not be achieved to reverse these antihyperalgesic and antiallodynic effects. These results suggest that the curative effect of agomelatine on neuropathic pain is mediated through rising synaptic catecholamine levels as well as through interactions with both α- and β-adrenoceptors. To our knowledge, this is the first study to show findings that indicate catecholaminergic system mediated antihyperalgesic and antiallodynic effects of agomelatine.

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“…Using an established drug has the advantage of reduced possibility of unknown adverse events. The therapeutic potential of rifampin is likely to be very broad, given the role of TLR4 in nonneuropathic chronic pain conditions (61, 62) and other pathologies (15, 63).…”

Section: Discussionmentioning

confidence: 99%

Rifampin inhibits Toll‐like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain

et al. 2013

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Rifampin has been used for the treatment of bacterial infections for many years. Clinically, rifampin has been found to possess immunomodulatory effects. However, the molecular target responsible for the immunosuppressive effects of rifampin is not known. Herein, we show that rifampin binds to myeloid differentiation protein 2 (MD-2), the key coreceptor for innate immune TLR4. Rifampin blocked TLR4 signaling induced by LPS, including NF-κB activation and the overproduction of proinflammatory mediators nitric oxide, interleukin 1β, and tumor necrosis factor α in mouse microglia BV-2 cells and macrophage RAW 264.7 cells. Rifampin's inhibition of TLR4 signaling was also observed in immunocompetent rat primary macrophage, microglia, and astrocytes. Further, we show that rifampin (75 or 100 mg/kg b.i.d. for 3 d, intraperitoneal) suppressed allodynia induced by chronic constriction injury of the sciatic nerve and suppressed nerve injury-induced activation of microglia. Our findings indicate that MD-2 is a important target of rifampin in its inhibition of innate immune function and contributes to its clinically observed immune-suppressive effect. The results also suggest that rifampin may be repositioned as an agent for the treatment of neuropathic pain.

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Streptozotocin-induced diabetic hyperalgesia in rats is associated with upregulation of toll-like receptor 4 expression

Cited by 39 publications

References 28 publications

Diabetic neuropathic pain: a role for testosterone metabolites

Diabetic neuropathic pain: a role for testosterone metabolites

Effect of subacute agomelatine treatment on painful diabetic neuropathy: involvement of catecholaminergic mechanisms

Rifampin inhibits Toll‐like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain

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