Arunachalam Muthuraman

Ameliorative effects of amiloride and pralidoxime in chronic constriction injury and vincristine induced painful neuropathy in rats

The present study was designed to investigate the ameliorative effects of clinically available drugs, with Na+/Ca2+ and Na+/H+ exchange inhibitory actions, in chronic constriction injury and vincristine induced painful neuropathy in rats. Sciatic nerve ligation and vincristine treatment (50 microg/kg for 10 days) was employed to induce neuropathy in rats. Paw pressure, von Frey hair, acetone drop, and tail heat immersion tests were performed to assess degree of mechano-hyperalgesia, mechano-allodynia, cold chemical allodynia and spinal thermal sensation respectively. Axonal degeneration of sciatic nerve was assessed histopathologically. The levels of thio-barbituric acid reactive species, reduced glutathione, and total calcium were determined to assess biochemical alterations. Amiloride (15 mg/kg i.p.), Na+/Ca2+ and Na+/H+ exchange inhibitor, and pralidoxime (20 mg/kg i.p.), Na+/Ca2+ exchange inhibitor, were administered for 10 consecutive days starting from the day of surgery or vincristine administration. Sciatic nerve ligation and vincristine treatment resulted in significant axonal degeneration, development of mechano-hyperalgesia, mechano-allodynia, cold chemical allodynia and spinal heat hyperalgesia and also resulted in rise in thio-barbituric acid reactive species, total calcium and decrease in reduced glutathione levels. Administration of amiloride and pralidoxime attenuated chronic constriction injury and vincristine induced axonal degeneration and reduction of nociceptive threshold along with reduction in calcium levels and oxidative stress. The observed anti-nociceptive effects of amiloride and pralidoxime may possibly be attributed to inhibition of Na+/Ca2+ and Na+/H+ exchangers with subsequent decrease in Ca2+ ions and oxidative stress.

Animal models of acute renal failure

The animal models are pivotal for understanding the characteristics of acute renal failure (ARF) and development of effective therapy for its optimal management. Since the etiology for induction of renal failure is multifold, therefore, a large number of animal models have been developed to mimic the clinical conditions of renal failure. Glycerol-induced renal failure closely mimics the rhabdomyolysis; ischemia-reperfusion-induced ARF simulate the hemodynamic changes-induced changes in renal functioning; drug-induced such as gentamicin, cisplatin, NSAID, ifosfamide-induced ARF mimics the renal failure due to clinical administration of respective drugs; uranium, potassium dichromate-induced ARF mimics the occupational hazard; S-(1,2-dichlorovinyl)-L-cysteine-induced ARF simulate contaminated water-induced renal dysfunction; sepsis-induced ARF mimics the infection-induced renal failure and radiocontrast-induced ARF mimics renal failure in patients during use of radiocontrast media at the time of cardiac catheterization. Since each animal model has been created with specific methodology, therefore, it is essential to describe the model in detail and consequently interpret the results in the context of a specific model.

Protective effect of Acorus calamus L. in rat model of vincristine induced painful neuropathy: an evidence of anti-inflammatory and anti-oxidative activity.

The study investigates the protective effect of Acorus calamus L. (AC) in vincristine-induced painful neuropathy. Vincristine (75μg/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy in rats. Various tests were performed to assess the degree of painful neuropathy at different days i.e., 0, 1, 7, 14, and 21st day. Sciatic nerve TNF-α, superoxide anion generation, total calcium, and myeloperoxidase activity level were also estimated after 21st day of study. Hydro-alcoholic extract of AC (HAE-AC, 100 and 200mg/kg, p.o.) and pregabalin (10mg/kg, p.o.) were administered for 14 consecutive days. Vincristine significantly induced neuropathic pain manifested in the terms of thermal hyperalgesia and allodynia (increase in hind paw licking, lifting or jumping from hot plate); mechanical hyperalgesia (increase in left hind paw lifting duration in pin-prick test) and allodynia (left hind paw withdrawal reflexes to non-noxious stimuli in Von Frey test); and sciatic functional index (analysis of footprints of the feet) along with rise in the levels of various biochemicals. HAE-AC attenuated vincristine induced behavioral, and biochemical changes comparable to that of pregabalin (positive control). HAE-AC attenuated vincristine induced painful neuropathy, which may be attributed to its multiple effects including anti-oxidative, anti-inflammatory, and calcium inhibitory actions.

Ameliorative effects of Ocimum sanctum in sciatic nerve transection-induced neuropathy in rats

OBJECTIVES The present study was aimed at investigating the ameliorative effect of Ocimum sanctum in sciatic nerve transection (axotomy)-induced peripheral neuropathy in rats. MATERIALS AND METHODS Sciatic nerve transection-induced axonal degeneration was assessed histopathologically. Paw pressure, Von Frey Hair, tail cold-hyperalgesia, motor in-coordination tests were performed to assess the extent of neuropathy. Biochemical estimations of thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH), and total calcium levels were also performed. Methanolic extract of Ocimum sanctum at different doses (50, 100 and 200mg/kg p.o.) was administered for 10 consecutive days starting from the day of surgery. RESULTS Administration of Ocimum sanctum attenuated sciatic nerve transection-induced axonal degeneration, reduction of nociceptive threshold and motor in-coordination. Moreover, it also attenuated axotomy-induced rise in TBARS, total calcium and decrease in GSH levels in a dose-dependent manner. CONCLUSION Anti-oxidant and calcium attenuating actions may be responsible for observed ameliorative effects of Ocimum sanctum in axotomy-induced neuropathy.

Attenuating effect of Acorus calamus extract in chronic constriction injury induced neuropathic pain in rats: an evidence of anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory effects

BackgroundAcorus calamus (family: Araceae), is an indigenous plant, traditionally it is used as an ingredient of various cocktail preparations and for the management of severe inflammatory disorders in Indian system of medicine. Present study investigated the attenuating role of Acorus calamus plant extract in chronic constriction injury (CCI) of sciatic nerve induced peripheral neuropathy in rats.MethodsHot plate, plantar, Randall Selitto, Von Frey Hair, pin prick, acetone drop, photoactometer and rota-rod tests were performed to assess degree of thermal, radiant, mechanical, chemical sensation, spontaneous motor activity and motor co-ordination changes respectively, at different time intervals i.e., day 0, 1, 3, 6, 9, 12, 15, 18 and 21. Tissue myeloperoxidase, superoxide anion and total calcium levels were determined after 21st day to assess biochemical alterations. Histopathological evaluations were also performed. Hydroalcoholic extract of Acorus calamus (HAE-AC, 100 and 200 mg/kg, p.o.) and pregabalin (10 mg/kg, p.o.) were administered from the day of surgery for 14 days.ResultsCCI of sciatic nerve significantly induced thermal, radiant, mechanical hyperalgesia and thermal, chemical, tactile allodynia, along with increase in the levels of superoxide anion, total calcium and myeloperoxidase activity. Moreover significant histological changes were also observed. HAE-AC attenuated CCI induced development of painful behavioural, biochemical and histological changes in a dose dependent manner similar to that of pregabalin serving as positive control.ConclusionsAcorus calamus prevented CCI induced neuropathy which may be attributed to its multiple actions including anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory actions.

Development of animal model for vasculatic neuropathy: Induction by ischemic-reperfusion in the rat femoral artery

Ischemic-reperfusion (I/R) is common in various pathological conditions like diabetic complication, complex regional pain syndrome type II (CRPS II), necrotizing vascular occlusive disease and trauma. We have developed an animal model of ischemic-reperfusion injury induced nociceptive sensory neuropathy in rats. The model was validated after 2, 4 and 6h of ischemia followed by prolonged reperfusion. The sensory behavioral assessment revealed thermal and mechanical hyperalgesia in paw and in tail which expressed the peripheral and central neuropathic pain respectively. We observed a decrease in the serum IL-10 and nerve conduction velocity and increase in the serum nitrate, malondialdehyde (MDA) and TNF-alpha levels in the 4 and 6h I/R groups in biochemical and electrophysiological evaluations. Histopathological study had revealed the decrease in nerve fiber density in the moderate and severe I/R groups. We selected the moderate (4h) ischemic-reperfusion injury as beneficial model because of the good correlation with clinical status for the development of neuropathy in human associated with severe pain disorders. This model can be used to explore pathophysiological mechanisms implied in the genesis of neuropathic pain and also to evaluate the new analgesic agents, peripheral neuro-vasoactive substances and neuroprotective drugs.

Antisecretory, antioxidative and antiapoptotic effects of montelukast on pyloric ligation and water immersion stress induced peptic ulcer in rat

In the present study, we tried to explore the mechanism of montelukast as an antiulcerogenic agent in pyloric ligation (PL) and water immersion stress (WIS) induced peptic ulcer. The ameliorative effects of montelukast (5, 10, and 20 mg/kg, p.o.) on gastric volume and total acidity were studied in PL model. We have investigated the alteration in the ulcerative index, thiobarbituric acid reactive substances, reduced glutathione, activity of myeloperoxidase, and total calcium level in both models. Estimation of DNA fragmentation by gel electrophoresis was also performed. Medium and higher doses of montelukast showed significant (p<0.05) ameliorative potential on all the above parameters as compared with omeprazole treated group. DNA fragmentation pattern clearly indicated the antiapoptotic effect of montelukast in preventing mucosal erosion in both models. Hence, the gastroprotective effect of montelukast may be attributed to its antisecretory, antioxidative along with its antiapoptotic effect.

Pharmacological evaluation of tacrolimus (FK-506) on ischemia reperfusion induced vasculatic neuropathic pain in rats

Background Ischemia reperfusion (I/R) is common in various pathological conditions like diabetic complication, rheumatic arthritis, necrotizing vascular occlusive disease and trauma. Methods We have evaluated the effect of tacrolimus (1, 2 and 3 mg/kg, p.o. for 10 consecutive days) on femoral arterial ischemic reperfusion (I/R) induced neuropathic pain in rats. Behavioral parameters (i.e. hot plate, radiant heat, acetone drop, tail heat hyperalgesia, tail flick and tail cold allodynia tests) were assessed at different time intervals (i.e. 0, 1, 4, 7, 10, 13 and 16th day) and biochemical analysis in serum and tissue samples were also performed along with histopathological studies. Results Behavioral pain assessment revealed increase in the paw and tail withdrawal threshold in tacrolimus treated groups against hyperalgesic and allodynic stimuli as compared to the sham control group. We observed a decrease in the serum nitrate and thiobarbituric acid reactive substance (TBARS) levels along with reduction in tissue myeloperoxidase (MPO) and total calcium levels, whereas, rise in tissue reduced glutathione levels in tacrolimus treated groups. However, significant results were obtained in medium and high dose treated group as compared to sham control group. Histopathological study had revealed the increase in the neuronal edema and axonal degeneration in the I/R group whereas, tacrolimus ameliorate these effects. Conclusion Our results indicate the anti-oxidative, anti-inflammatory and calcium modulatory actions of tacrolimus. Therefore, it can be used as a therapeutic agent for the treatment of vascular inflammatory related neuropathic pain.

Neuroprotective effect of saponin rich extract of Acorus calamus L. in rat model of chronic constriction injury (CCI) of sciatic nerve-induced neuropathic pain

ETHNOPHARMACOLOGICAL RELEVANCE Traditionally, Acorus calamus has been used for the treatment and management of headache, migraine, body ache and severe inflammatory pain in the Unani, Ayurveda and Indian system of medicine. AIM OF THE STUDY Present study focuses on the evaluation of saponin rich extract of Acorus calamus (SRE-AC) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain and neuronal functional changes in rats. MATERIALS AND METHODS The pain sensitive tests, i.e., thermal and mechanical hyperalgesia and sciatic functional index test, were performed on the different days, i.e., days 0, 1, 7, 14, and 21. The motor and sensory nerve conduction velocity was also measured on the 21st day. Tissue total protein, superoxide anion generation, total calcium, myeloperoxidase and TNF-α levels were estimated to assess biochemical changes. Histopathological evaluations were also performed. SRE-AC (20 and 40 mg/kg) and pregabalin (10mg/kg, serving as a positive control) were administered orally for 14 consecutive days from the day of surgery. RESULTS CCI produced significant (P<0.05) increase in thermal and mechanical hyperalgesia, rise in sciatic functional index, decrease in nerve conduction velocity, along with biochemical and histopathological changes. Oral administration of SRE-AC and pregabalin significantly (P<0.05) ameliorated CCI-induced nociceptive pain threshold, sciatic functional and electrophysiological changes in a dose dependent manner. Further, tissue biochemical and histopathological changes were also attenuated. CONCLUSION SRE-AC has shown ameliorative effect in CCI-induced neuropathic pain which may be attributed to its multiple actions including anti-oxidative, anti-inflammatory and neuroprotective actions.

Drug Therapy of Neuropathic Pain: Current Developments and Future Perspectives

Understanding mechanism of neuropathic pain is too complex and involves both peripheral and central pathophysiological phenomenon. Accordingly the treatment of neuropathic pain is also very complex and is unsatisfactory. The present review attempts to discuss the currently employed pharmacological agents for the management of neuropathic pain including anti-depressants, anti-convulsants, NMDA receptor antagonists, topical & local anesthetics, and upload analgesics. However, the existing pharmacotherapy has marginal efficacy and significant side effects. The review also gives an insight into various pharmacological agents with potential neuropathic pain attenuating properties in experimental models that include NSAIDs, corticosteroids, ion channel blockers (Ca(2+), Na(+), K(+), and TRP channel); ion exchange modulators (NCE and NHE); ion/molecule transport modulators (NKCC-1 and glycine); receptor modulators (kinin, histamine, 5-HT1A, dopamine, alpha & beta adrenergic, purinergic, excitatory amino acid, sigma, ORL1, endothelin, melanocortin, ephrin and PAR); enzyme inhibitors (cytosolic kinase, metalloproteinase, protease, vasopeptidase, D-amino acid oxidase, fatty acid amide hydrolase, aldose reductase and sorbitol dehydrogenase); other ligands (AGE, RAGEs, neuropeptides, neurotrophic factor, complement cascade, cytokine, glial cell & gap junction, nitrous oxide, growth factor, cell adhesion molecule and neuronal sprouting molecule). Moreover, some advanced therapeutic approaches such as neuronal cell transplantation, stem cell therapy, anti-sense oligonucleotide and recombinant therapy have also been dicussed.