Autophagy and anti-inflammation ameliorate diabetic neuropathy with Rilmenidine

Purpose: To evaluate the neuroprotective effects of Rilmenidine on diabetic peripheral neuropathy (DPN) in a rat model of diabetes induced by streptozotocin (STZ). Methods: STZ (60 mg/kg) was administered to adult Sprague-Dawley rats to induce diabetes. On the 30th day after STZ administration, electromyography (EMG) and motor function tests confirmed the presence of DPN. Group 1: Control (n = 10), Group 2: DM + 0.1 mg/kg Rilmenidine (n = 10), and Group 3: DM + 0.2 mg/kg Rilmenidine (n = 10) were administered via oral lavage for four weeks. EMG, motor function test, biochemical analysis, and histological and immunohistochemical analysis of sciatic nerves were then performed. Results: The administration of Rilmenidine to diabetic rats substantially reduced sciatic nerve inflammation and fibrosis and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves from saline-treated rats revealed increased perineural thickness, HMGB-1, tumor necrosis factor-α, and a decrease in nerve growth factor (NGF), LC-3. In contrast, Rilmendine significantly inhibited inflammation markers and prevented the reduction in NGF expression. In addition, Rilmenidine significantly decreased malondialdehyde and increased diabetic rats' total antioxidative capacity. Conclusions: The findings of this study suggest that Rilmenidine may have therapeutic effects on DNP by modulating antioxidant and autophagic pathways.

Comparison of antiallodynic effect of intrathecal morphine, brimonidine and rilmenidine between neuritis and ligation injury induced neuropathic pain / 대한마취과학회지

BACKGROUND: Mechanical allodynia is generally resulted from nerve damage by direct injury or inflammation. Thus, this study was designed to compare the antiallodynic effect of morphine, brimonidine and rilmenidine in two models of neuropathic pain, that is, induced by nerve ligation and neuritis. METHODS: Rats were prepared with tight ligation of the L5/L6 spinal nerves (SNL group) or with Freund's complete adjuvant (FCA) administration evoked sciatic inflammatory neuritis (SIN group). Antiallodynic effects by intrathecal morphine, brimonidine and rilmenidine were measured by applying von Frey filaments to the lesioned hind paw. Thresholds for withdrawal response were assessed and converted to % MPE to obtain an effective dose 50% (ED 50) and a dose response curve. RESULTS: Either SNL group or SIN group showed marked mechanical allodynia in the lesioned hind paw. Antiallodynic effects of morphine were different between two groups. That is ED 50 was 0.16 microgram (SIN) and 8.12 microgram (SNL), and dose response curve of the SIN group shifted left from that of the SNL group. The difference between SIN and SNL groups was statistically significant (P < 0.05). With the brimonidine or rilmenidine administration, ED 50 s were 0.12 microgram (SNL) and 0.37 microgram (SIN) and 2.16 microgram (SIN) and 11.46 microgram (SNL), respectively. And the shift to left of dose response curve from the SNL group is more prominent with rilmenidine administration. CONCLUSIONS: These results suggest morphine and rilmenidine showed a better effect on reducing the mechanical allodynia induced by FCA administration.

The Effect of Rilmenidine Pretreatment on the Cardiovascular Toxicity Caused by Intravenous Bupivacaine by Autonomic Nervous System Analysis in Anesthetized Cats / 대한마취과학회지

BACKGROUND: This study was designed to assess the effects of rilmenidine on the autonomic nervous system, and to evaluate whether it prevents bupivacaine-induced cardiovascular toxicity during intravenous bupivacaine infusion in anesthetized cats. METHODS: Thirty male cats were randomly divided into a control group (n = 15) and a rilmenidine group (n = 15). Following the injection of rilmenidine (10microgram/kg), systolic blood pressures (SBP) and R-R intervals (RRI) were recorded for 5 minutes. Then power spectral analyses of the SBP and RRI, and transfer function analysis were conducted to evaluate the autonomic nervous system. During the infusion of bupivacaine (0.5 mg/kg/min), blood pressures, heart rates, times to reach each events, and bupivacaine doses were measured at the first QRS modification, the first dysrhythmia, at 25% (HR25) and 50% reductions in baseline heart rate, and at 25% and 50% reductions in baseline mean arterial pressure and at final systole. RESULTS: The high frequency (HF) power of heart rate variability (HRV) was significantly elevated in the rilmenidine group versus the control group. Magnitude HF was significantly higher in the rilmenidine group than in the control group. The onset of dysrhythmia correlated significantly with the HFs of HRV and baroreflex sensitivity (BRS). Except for HR25, the rilmenidine group showed significantly higher bupivacaine doses and delayed event onsets versus the control group. CONCLUSIONS: We suggest that pretreatment with rilmenidine delays the onset of dysrhythmia by increasing vagal tone and BRS and by reducing cardiovascular toxicity when bupivacaine is infused continuously to isoflurane anesthetized cats.

Participação do óxido nítrico no efeito sedativo e antinociceptivo dos agonistas alfa 2 - adrenérgicos / nvolvement of nitric oxide in the sedative and antinociceptive alpha 2 agonist - adrenergic

O mecanismo do efeito sedativo da clonidina (CLO), um agonista alfa2 adrenérgico não é claro. Como a ativação dps receptores alfa2 adrenérgico induz a liberação de óxido nítrico (NO) das células endoteliais, restamos a hipótese de que o efeito sedativo e antinociceptivo da CLO sistêmica dependeria de mecanismos relacionados a via NOGMPc. P 7NI reduziu significativamente o tempo de sono induzido pela clonidina...A CLO (3-120 mg/kg) and RIL induziram efeito antinociceptivo dose-dependente no teste das contorções abdominais e TFL. O efeito antinociceptivo da CLO foi significativamente reduzido pela inibição da NO syntase and guanylyl ciclase. O efeito da RIL também foi reduzido pelo 7-NI. O efeito antinociceptivo da morfina foi inibido pela naloxona, que não inibiu o efeito da CLO. Nossos resultados sugerem que o efeito da CLO sistêmica não envolve receptor opióide e é modulado por uma via NO-GMPc.

The Effect of alpha2 Adrenergic Agonists and Norepinephrine on Mechanical Allodynia by Freund's Complete Adjuvant Induced Inflammation in Rats / 대한마취과학회지

BACKGROUND: The Freund's complete adjuvant (FCA)-induced inflammation may produce allodynia against a touch stimulus. The antiallodynic effects of brimonidine, a new selective alpha2 receptor agonist, and of rilmenidine, a new more selective imidazoline receptor agonist, have not been evaluated in rats with FCA induced inflammation. Therefore, we investigated the sympathetic component of mechanical allodynia after the development of allodynia secondary to FCA-induced inflammation in rats. METHODS: A lumbar intrathecal catheter was implantated in male Sprague Dawley rats. Inflammation was induced by the intradermal injection of 0.15 ml FCA under enflurane anesthesia. Using Von Frey filaments, the antiallodynic effects of intrathecal (I.T.) brimonidine (1, 3 microgram), rilmenidine (30, 100 microgram) and saline were examined. In antagonistic study intrathecal yohimbine 30 microgram and rauwolscine 30 microgram were administered to investigate the reversal of the antiallodynic effect by each agonist. We also examined the effects of intradermal norepinephrine followed by I.T. brimonidin, rilmenidine or saline on the withdrawal threshold of rats secondary to allodynia induced by FCA. RESULTS: I.T. brimonidine or rilmenidine produced dose-dependent antiallodynic effect and which were moderately antagonized by I.T. yohimbine or rauwolscine. Intradermal norepinephrine produced a reduction in the withdrawal threshold in rats. CONCLUSIONS: Our results suggest that a sympathetic component is likely to be involved in the mechanism of allodynia secondary to FCA-induced inflammation.

Effect of Rilmenidine and Clonidine Premedication on the Cardiovascular Action of Phenylephrine and Nitroprusside in Rats / 대한마취과학회지

BACKGROUND: Patients premedicated with clonidine often present with hypotension and bradycardia. The hypotensive patient premedicated with clonidine should be given a vasopressor to treat hypotension. In these patients, an augmented vasopressor response would be shown. Rilmenidine as an allied drug of clonidine is an antihypertensive agent with selectivity for the imidazoline receptor that acts centrally by reducing sympathetic overactivity. This study was designed to evaluate the effect of clonidine and rilmenidine on changes in mean blood pressure and baroreflex sensitivity following phenylephrine and nitroprusside administration. METHODS: Sixty Sprague-Dawley rats were assigned randomly into one of three groups, control group (n = 20), clonidine group (n = 20) or rilmenidine group (n = 20). Saline (control group), clonidine 30ng/kg (clonidine group) or rilmenidine 300ng/kg (rilmenidine group) were intraperitoneally injected respectively. Following the injection, a phenylephrine and nitroprusside test were performed. RESULTS: The percent change in mean blood perssure from the baseline values in the control group, clonidine group and rilmenidine group were 35 +/- 18%, 54 +/- 17% and 62 +/- 38%, respectively. There was no difference between the baroreflex sensitivity in the pressure (phenylephrine) test (0.94 +/- 0.43, vs 1.05 +/- 0.62, vs 1.13 +/- 0.59 msec/mmHg). In contrast, the slopes of the depressor (nitroprusside) test were decreased in rats receiving clonidine and rilmenidine (0.51 +/- 0.34, vs 0.12 +/- 0.08, vs 0.18 +/- 0.09 msec/mmHg, P < 0.05). CONCLUSIONS: It is concluded that the rilmenidine and clonidine groups showed a more augmented pressure response to vasopressors than the control group. Therefore, the decreased dosage of vasopressors is recommended to treat hypotension in rilmenidine premedicated patients.

The Effect of Intradermal Norepinephrine on Allodynia in a Neuropathic Pain Rat Model / 대한마취과학회지

BACKGROUND: A spinal nerve ligation (SNL) injury may produce a neuropathic pain syndrome that includes tactile allodynia. This pain state may be diminished by sympathectomy. Intradermal (I.D.) injection of norepinephrine (NE) evokes pain in patients with sympathetically maintained pain. Recently, we reported the effect of intrathecal (I.T.) brimonidine and rilmenidine on the sympathetic nervous system. Therefore, we conducted a behavioral test to investigate the effects of sympathetic stimulation by I.D. NE on mechanical allodynia in rats with a SNL injury. METHODS: Male SD rats were prepared with ligation of the left lumbar 5th and 6th spinal nerves and lumbar I.T. catheter implantation. NE 10ng I.D. was administered in normal and SNL rats to investigate the change of cutaneous sensitivity to tactile stimuli. NE 30ng I.D. was administered before and after I.T. injection of brimonidine 3ng and rilmenidine 30ng in SNL rats. Using a von Frey hair (VFH) test, we examined the effects of NE on the withdrawal threshold. Allodynic thresholds for the withdrawal response of the lesioned hindpaw to VFH stimuli were assessed. RESULTS: Intradermal NE produced a reduction of the withdrawal threshold in normal and allodynic rats. An allodynic state induced by a SNL was aggravated by NE. In allodynic rats, the baseline threshold of a lesioned left hindpaw was markedly low and such a state was maintained during the behavioral experiment. The antiallodynic effects of I.T. brimonidine and rilmenidine were produced in both pre- and post-treatment of NE. CONCLUSIONS: The results suggest that a sympathetic component is likely involved in the mechanism of mechanical allodynia produced by a SNL injury.

The Effect of alpha2 Adrenoceptors and Imidazoline Receptors on the Mechanical Allodynia in Rats with Nerve Ligation Injury / 대한마취과학회지

BACKGROUND: Clonidine, an alpha2 adrenoceptor agonist, has been known to have an antiallodynic effect in many animal and human studies. Clonidine, however, acts on imidazoline receptors as well as alpha2 adrenoceptors. Recently, the effect of clonidine on the symapthetic nervous system was reported to be mediated via the activation of the imidazoline receptor system but not the alpha2 adrenergic receptor system. Therefore, we conducted a behavioral test to investigate the effects of alpha2 adrenoceptors and imidazoline receptors on mechanical allodynia in rats with spinal nerve ligation (SNL) injury. METHODS: Male Sprague Dawley rats were prepared with tight ligation of the left lumbar 5th and 6th spinal nerves and chronic lumbar intrathecal catheter implantation for drug administration. Using a von Frey hair (VFH) test, we examined the effects of intrathecal (IT) brimonidine (0.03 - 3 microgram), clonidine (3 - 10 microgram), and rilmenidine (1 - 30 microgram) in SNL rats. Measurements of the baseline value VFH test was conducted at each dose to compare with the preoperative state. In addition, an antagonistic study with rauwolscine or yohimbine was performed to investigate the reversal of antiallodynic effects of each agonist. Allodynic thresholds for the withdrawal response of the left lesioned hindpaw to VFH stimuli were assessed and converted to %MPE. RESULTS: The antiallodynic effects of brimonidine, clonidine, and rilmenidine were produced in a dose dependent manner. The antiallodynic effects of IT brimonidine but not rilmenidine were significantly antagonized by alpha2 antgonists rauwolscine and yohimbine (P < 0.05). CONCLUSIONS: The results suggest that mechanical allodynia produced by a SNL injury is reduced by an imidazoline receptor agonist as well as alpha2 adrenergic receptor agonists and sympathetic activation is more likely mediated by spinal imidazoline receptors.