|Year : 2014 | Volume
| Issue : 2 | Page : 82-88
Ameliorative effect of ethyl pyruvate in neuropathic pain induced by chronic constriction injury of sciatic nerve
Varsha J. Bansode1, Neeraj S. Vyawahare2, Neeraj B. Munjal2, Pradip N. Gore3, Pushpendra S. Amrutkar1, Snehashree R. Sontakke1
1 Department of Pharmacology, All India Shree Shivaji Memorial Society's College of Pharmacy, Pune, Maharashtra, India
2 Department of Pharmacology, Padmashree Dr. Dnyandeo Yashwantrao Patil College of Pharmacy, Pune, Maharashtra, India
3 Department of Pharmacology, Indira Gandhi Government Medical College and Hospital, Nagpur, Maharashtra, India
|Date of Web Publication||20-May-2014|
Varsha J. Bansode
Department of Pharmacology, All India Shree Shivaji Memorial Society's College of Pharmacy, Near RTO, Kennedy Road, Pune - 411 001, Maharashtra
Source of Support: None, Conflict of Interest: None
Objective: The present study was designed to investigate the ameliorative effects of ethyl pyruvate (EP) in chronic constriction injury (CCI)-induced painful neuropathy in rats. Materials and Methods: EP 50 and 100 mg/kg was administered for 21 consecutive days starting from the day of surgery. The effects of EP in the paw pressure, acetone drop, and tail heat immersion tests were assessed, reflecting the degree of mechanical hyperalgesia, cold allodynia, and spinal thermal sensation, respectively. Axonal degeneration of the sciatic nerve was assessed histopathologically. The levels of thiobarbituric acid reactive species, reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) were determined to assess oxidative stress. Key Findings: Administration of 50 and 100 mg/kg EP attenuated the reduction of nociceptive threshold in the paw pressure, acetone drop, and tail heat immersion tests. EP 100 mg/kg significantly attenuated reactive changes in histopathology and increase in oxidative stress. Conclusion: EP 100 mg/kg showed beneficial activity against nerve trauma-induced neuropathy. Hence, it can be used as a better treatment option in neuropathic pain (NP). The observed antinociceptive effects of EP may possibly be attributed to its antioxidant and anti-inflammatory activity.
Keywords: Anti-inflammatory, antioxidant, chronic constriction injury, ethyl pyruvate
|How to cite this article:|
Bansode VJ, Vyawahare NS, Munjal NB, Gore PN, Amrutkar PS, Sontakke SR. Ameliorative effect of ethyl pyruvate in neuropathic pain induced by chronic constriction injury of sciatic nerve. Indian J Pain 2014;28:82-8
|How to cite this URL:|
Bansode VJ, Vyawahare NS, Munjal NB, Gore PN, Amrutkar PS, Sontakke SR. Ameliorative effect of ethyl pyruvate in neuropathic pain induced by chronic constriction injury of sciatic nerve. Indian J Pain [serial online] 2014 [cited 2019 Nov 17];28:82-8. Available from: http://www.indianjpain.org/text.asp?2014/28/2/82/132845
| Introduction|| |
The International Association for the Study of Pain (IASP) defines neuropathic pain (NP) as pain ''initiated or caused by a primary lesion or dysfunction in the nervous system.'' This type of pain is generally described as a tingling, stinging, or burning sensation and can have all degrees of severity. Increased pain from stimuli that ordinarily produce lower levels of pain, known as hyperalgesia, is considered a symptom of NP. A similar condition, allodynia, is undergoing a severe pain response from non-painful stimuli.  In addition, oxidative stress is an important determinant of degenerative and painful pathological conditions in peripheral nerve fibers. Increased reactive oxygen species (ROS) in dorsal horn neurons may contribute to central sensitization in neuropathic rats.  The chronic constriction injury (CCI)-induced painful neuropathy in rats model was selected because the physical trauma may be the most common cause of NP. Trauma caused by auto accidents, sport injuries, and falls can result in nerves being partially damaged to completely severed, crushed, and stretched. Nerve injury sometimes leads to chronic NP associated with neuroimmune activation and neuroinflammation in both the peripheral and central nervous systems.  NP greatly affects quality of life. In 5% of NP cases, it may be severe and those numbers are increasing. It is widely treated with antidepressants like amitryptiline, nortryptiline, N-methyl-D-aspartate (NMDA) antagonists, and anticonvulsants like carbamazepine and gabapentine, but current treatment options only achieve clinically significant (greater than 50%) pain relief in less than 50% of patients and are associated with suboptimal side effect profiles. To overcome these drawbacks, novel treatment options would be desirable. 
Pyruvic acid (CH 3 COCOOH), the final product of glycolysis, is present in cells and extracellular fluids as its conjugate anion, pyruvate. Pyruvic acid is the starting substrate for the tricarboxylic acid (TCA) cycle. , Ethyl pyruvate (EP) is a simple derivative of endogenous metabolite, pyruvic acid. EP was developed in order to attenuate problems related to the instability of aqueous solution of pyruvate. Some findings indicated that the EP is more effective than pyruvate. Treatment with EP has been shown to improve survival and or ameliorate organ dysfunction in a wide variety of preclinical models of critical illnesses, like severe sepsis, acute respiratory distress syndrome, acute pancreatitis, traumatic brain injury, and so forth. In the NP, oxidative stress and inflammation increases and causes pain. As EP is proven antioxidant and anti-inflammatory compound in various models by virtue of its mechanisms like inhibition of redox-mediated cellular damage, cytoprotection, inhibition of apoptosis, and inhibition of inflammation. , It may be helpful in reducing NP in animals. It remains to be determined whether EP can be used successfully to treat NP.
| Materials and Methods|| |
Male Wistar albino rats were used for the study. Animals were maintained at 25 ± 2°C, relative humidity of 45-55%, and under the standard environmental conditions (12-h light: 12-h dark cycle). They were allowed to take standard laoratory feed (Amrut feed, Pune) and water ad libitum. All the experimental procedures and protocols used in this study were reviewed and approved by the Institutional Animal Ethical Committee (IAEC) of All India Shree Shivaji Memorial Society's (AISSMS) College of Pharmacy, Pune, constituted under Committee for Purpose of Control and Supervision of Experiments on Animals (CPCSEA), approval number (CPSEA/IAEC/PC-02/05-2K11). The ethical guidelines were strictly followed during the study.
Chemicals and Drugs
Accurately weighed quantity of EP (Anand Agencies, Pune) was dissolved in the distilled water to prepare appropriate stock solution, i.e. EP 50 mg/ml and EP 100 mg/ml, respectively. Ketamine and xylazine (Chandra Bhagat Pharma Pvt. Ltd, Mumbai) were used as anesthetic agents.
Rats were deeply anesthetized with intraperitonial (ip) injection of ketamine (70 mg/kg) and xylazine (10 mg/kg). The hair of rat's lower back and thigh was shaved. The skin of lateral surface of left thigh was incised and a cut was made directly through the biceps femoris muscle to expose the sciatic nerve, and four ligatures (silk 4-0) were placed around the nerve proximal to trifurcation, with an approximate distance of 1 mm between each ligature. Length of the nerve thus affected was 4-5 mm. After performing nerve ligation, muscles and skin was immediately sutured in layers, and topical antibiotic (povidone iodine) was applied. All the surgical procedures were carried out under sterile conditions. ,
Animals were divided in five groups, each containing six animals. Two doses EP (50 and 100 mg/kg) were studied.
Group I (control group)
Rats in this group were not subjected to any surgical procedure and were kept for 21 days. After subjecting rats to CCI, distilled water (1 mg/kg) was administered orally for 21 consecutive days. Behavioral tests were performed to assess nociceptive threshold on different days, i.e. days zero, seven, 14, and 21. All the animals were sacrificed at the end of the 21 st day, and biochemical analysis with histopathological examinations was carried out.
Group II (sham control group)
Rats in this group were subjected to surgical procedure to expose left sciatic nerve without any nerve ligation. After subjecting the rats to CCI, distilled water (1 mg/kg) was administered orally for 21 consecutive days. Behavioral tests, biochemical parameters, and histopathological examinations were performed as mentioned in group I.
Group III (CCI group)
Rats in this group were subjected to surgical procedure, to expose and ligate left sciatic nerve as described earlier. After subjecting the rats to CCI, distilled water (1 mg/kg) was administered orally for 21 consecutive days. Behavioral tests, biochemical parameters, and histopathological examinations were performed as mentioned in group I.
Group IV (EP 50 mg/kg in CCI)
Rats in this group were subjected to surgical procedure, to expose and ligate left sciatic nerve. After subjecting the rats to CCI, EP (50 mg/kg) was administered orally for 21 consecutive days. Behavioral tests, biochemical parameters, and histopathological examinations were performed as mentioned in group I.
Group V (EP 100 mg/kg in CCI)
Rats in this group were subjected to surgical procedure, to expose and ligated left sciatic nerve. After subjecting the rats to CCI, EP (100 mg/kg) was administered orally for 21 consecutive days. Behavioral tests, biochemical parameters, and histopathological examinations were performed as mentioned in group I.
| Behavioral Examination|| |
Assessment of Thermal Hyperalgesia
Tail-immersion (hot water) test
Spinal thermal sensitivity was assessed by the tail-immersion test. Tail thermal hyperalgesia was noted by immersion of terminal part of tail (1 cm) in water, maintained at a temperature of 52.5 ± 0.5°C. The duration of the tail withdrawal reflex was recorded as response to thermal stimulation; a cutoff time of 15 s was maintained during each response. Shortening of the tail withdrawal time indicated hyperalgesia. 
Assessment of Mechanical Hyperalgesia
Paw pressure withdrawal test (Randall-Salitto test)
In paw pressure withdrawal test, nociceptive flexion reflexes were quantified using digital Randall-Selitto apparatus (IITC Life Science, USA). Linearly increasing pressure, with the cutoff of 250g to avoid tissue injury, was applied to the center of hindpaw. When animal displayed pain by withdrawal of the paw, vocalization, or overt struggling; the applied paw pressure was registered by an analgesia meter and expressed in mass units (grams). ,
Assessment of Cold Allodynia
Paw cold-allodynia (acetone drop test)
For paw cold-allodynia, spray 100 μl of acetone onto the surface of the paw, without touching skin. The response of rat to acetone was recorded for 20 s and was graded as a 4-point scale like 0 for no response; 1 for quick withdrawal, flick, or stamp of the paw; 2 for prolonged withdrawal or repeated flicking; and 3 for repeated flicking of the paw with licking of the paw. With a gap of 5 min, acetone was applied thrice to the hind paw, the individual scores were noted in 20-s interval, and were added to obtain a single score over a cumulative period of 60 s. The minimum score was 0, whereas the maximum possible score was 9. 
Preparation of homogenate
Animals were sacrificed by ether anesthesia and the sciatic nerve was isolated immediately. The uniformity among the different nerve samples was maintained by taking the constant weight of the respective samples. The excised sciatic nerve homogenate (10% w/v) was prepared with 0.1 M Tris-HCl buffer (pH 7.4). The tubes with homogenate were kept in ice water for 30 min and centrifuged at 4°C (2500 rpm, 10 min). The supernatant of homogenate was separated and employed for estimations of extent of lipid peroxidation, malondialdehyde (MDA), the levels of reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) enzymes. ,
Assay of lipid peroxidation
The estimation of lipid peroxidation in the sciatic nerve was done by measuring the thiobarbituric acid reactive substances by the method of Bohme et al., 1977.  The absorbance was measured spectrophotometrically at 532 nm. The concentration was expressed in terms of nM of MDA/g of tissue.
Assay of reduced GSH levels
The estimation of reduced GSH levels in the sciatic nerve was done by the method of Ellman, 1959.  The absorbance was measured spectrophotometrically at 412 nm. The concentration was expressed in terms of microgram of GSH/g of tissue.
Estimation of CAT activity
The estimation of CAT activity in the sciatic nerve was done by the method of Luck, 1971.  The change in absorption was measured at 240 nm for 2-3 min. The concentration was expressed in μM of H 2 O 2 /g of tissue/min.
Estimation of SOD activity
The estimation of SOD activity in the sciatic nerve was done by the method of Misra and Fridovich, 1972.  The change in absorption was measured at 480 nm for 3 min, with 60 s interval. The concentration was expressed in U/g of tissue.
Histology samples of sciatic nerve were paraffin embedded, cut to 4-mm thickness and stained by the Hematoxylin and Eosin (H and E). Sections were observed under light microscope (400×) for axonal degeneration and histopathological changes.
The results are expressed as mean + Standerd Error of Means (SEM) Statistical analysis was done using INSTAT graph pad software. Comparison between the groups were made with one way analysis of variance (ANOVA) followed by Dunnett's test.
| Results|| |
Effect of EP Treatment on Thermal Hyperalgesia
Tail immersion (hot water) test
As shown in [Figure 1], the neuropathic induction group after CCI of sciatic nerve showed significant (P < 0.01) duration dependent reduction in reaction time at 14 th and 21 st day as compared with sham control group. The administration of EP 50 mg/g showed significant (P < 0.05) increase in reaction time at 21 st day only. The administration of EP 100 mg/g showed significant (P < 0.05) and (P < 0.01) increase in reaction time at 14 th and 21 st day, respectively, when compared with neuropathic induction group [Figure 1].
|Figure 1: Effect of EP treatment on thermal nociceptive threshold. EP: Ethyl pyruvate|
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Effect of EP Treatment on Mechanical Hyperalgesia
Paw pressure withdrawal test
As shown in [Figure 2], neuropathy induction group showed significant (P < 0.01) duration dependent reduction in the paw pressure withdrawal threshold at 14 th and 21 st day as compared with sham control group. The administration of EP 50 mg/g showed significant (P < 0.05) increase in paw pressure withdrawal threshold at 21 st day only. But, EP 100 mg/g showed significant (P < 0.05) and (P < 0.01) increase in paw pressure withdrawal threshold at 14 th and 21 st day of treatment, respectively, as compared with neuropathy induction group [Figure 2].
|Figure 2: Effect of EP treatment on paw pressure withdrawal thresholds. EP: Ethyl pyruvate|
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Effect of EP Treatment on Cold Allodynia
Acetone drop test
As shown in [Figure 3], the allodynia score was significantly (P < 0.01) increased at 21 st day in neuropathy induction group than sham control group. The administration of EP 50 mg/g showed significant (P < 0.05) effect at 21 st day only. The administration of EP 100 mg/g modulate increased allodynia score significantly (P < 0.05) and (P < 0.01) at 14 th and 21 st day, respectively, as compared with neuropathy induction group [Figure 3].
Histopathology of Sciatic Nerve
A shown in [Figure 4], photographs show vacuolar changes (white arrow), cellular infiltration (gray arrow), and necrosis and degeneration (black arrow) in H and E stain sections of sciatic nerve under 400. (A) Control group, pathological grade-0, (B) sham control, pathological grade-0, (C) CCI induction group, pathological grade-++++, (D) CCI induction+EP 50 mg/kg, pathological grade-+++, (E) CCI induction+EP 100 mg/kg, pathological grade-++. Rats subjected to CCI showed morphological alterations like necrosis of neurons, cellular infiltration along with nerve fiber dearrangement. Treatment with EP 100 mg/kg significantly attenuated these reactive changes [Figure 4].
Biochemical Parameters of Sciatic Nerve Homogenate
As shown in [Table 1], a significant (P < 0.01) increase in MDA level along with decrease in GSH, CAT, and SOD concentration was found in neuropathy induction group. The administration of EP 50 mg/kg for 21 days significantly (P < 0.05) attenuated increase in MDA level but without any decrease in GSH, CAT, and SOD concentartion. The administration of EP 100 mg/kg for 21 days significantly (P < 0.01) attenuated increase in MDA level and significantly (P < 0.05) decreased GSH, CAT, and SOD concentartion [Table 1].
|Table 1: Effect of EP on oxidative markers in sciatic nerve homogenate against CCI-induced peripheral neuropathy in rat |
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| Discussion|| |
NP has been described as "the most terrible of all tortures which a nerve wound may inflict". To overcome drawbacks of current treatments in NP, novel treatment options would be desirable.  The extensive literature survey for various scientific documentation indicated pyruvate derivative, i.e. EP is biologically active and can be used as a good target to improve overall therapeutic outcome. However, it has not been scientifically documented so far for its effect in NP, in light of which the present investigation was carried out. In the present investigation, EP proposed to be an antioxidant and anti-inflammatory and was screened for its effect in the NP using CCI of sciatic nerve in rats.
In particular, demonstration of hyperalgesia to noxious thermal and mechanical stimuli and allodynia to cold are used as outcome measures after CCI of sciatic nerve in rats. , In the present study, CCI lead to significant development of heat hyperalgesia, mechanical hyperalgesia, and cold allodynia, assessed on 21 st day after surgery. Treatment with EP 50 mg/kg and EP 100 mg/kg significantly increases paw withdrawal threshold in mechanical hyperalgesia, response time in heat hyperalgesia and decreases allodynia score in cold allodynia, in dose-dependent manner. CCI-induced alterations in pain perception in response to noxious as well as non-noxious stimuli were attenuated by EP significantly in dose-dependent manner.
In the CCI model of rat neuropathic pain, it has been shown that oxidative stress as well as the antioxidants SOD and reduced GSH are important determinants of neuropathological and behavioral consequences.  Recently, it has become clear that inflammatory and immune mechanisms both in the periphery and the central nervous system play an important role in NP. Incomplete nerve damage by a CCI of the sciatic nerve induces pain and is accompanied by a profound local inflammatory reaction that includes infiltration of hematogenous immune cells and the induction of various factors like cytokines and chemokines. These mediators promote neuroimmune activation and can sensitize primary afferent neurones and contribute to pain hypersensitivity. Inflammatory cells such as mast cells, neutrophils, macrophages, and T lymphocytes have all been implicated, as have immune-like glial cells such as microglia and astrocytes. 
Peripheral nervous system has a rich source of lipids and may be predominant target of free radical-mediated lipid peroxidation. GSH acts as an antioxidant and in present study we observed a significant decrease in GSH levels in sciatic nerve that represents its increased utilization due to oxidative stress. CAT and SOD is one of the major scavenging enzymes that remove toxic free radicals in vivo. CAT protecting the cellular constituents from oxidative damage decreased significantly in CCI rats and probably could be associated with oxidative stress or decreased antioxidant defense potential.  In the present investigation, CCI induced-neuropathy having rise in oxidative stress evaluated in terms of rise in thiobarbituric acid-reactive substances and decrease in reduced GSH, CAT, and SOD levels. These results are in line with an earlier report, suggesting the key role of oxidative stress in CCI-induced neuropathy.  In turn, free radicals are documented to induce tissue injury and NP. , Further, administration of EP 50 mg/kg and 100 mg/kg attenuated CCI-induced increase in MDA levels in dose-dependent manner. Oxidative stress-induced decrease in GSH, CAT, and SOD levels attenuated by coadministration of EP 100 mg/kg. Therefore, it may be tentatively proposed that EP-attenuated increase in free radical generation is responsible for antinociceptive effects, noted in the present investigation.
Histopathology is an important tool to evaluate protective effect of the drugs acting on the damaged or necrotic cells produced by the induction of neuropathy. At the constricted nerve segment, we observed a heterogeneous distribution of degenerative fibers, although damaged axons were mostly concentrated at the periphery of the nerve in histopathological findings of sciatic nerve. Vacuolar changes and degeneration of fibers were more prominently found in CCI of sciatic nerve. These changes were attenuated significantly by EP 50 and EP 100 mg/kg in dose-dependent manner.
All of the above findings suggest that EP 100 mg/kg is more effective in attenuation of heat, mechanical hyperalgesia, and cold allodynia in chronic constriction-induced neuropathy of sciatic nerve. It was also found that EP 100 mg/kg was effective in scavenging ROS and attenuates oxidative stress. It was also found that the histopathological changes occur in neuropathy induction by nerve trauma were significantly reversed by EP 100 mg/kg.
| Conclusion|| |
To conclude, EP 100 mg/kg has potential for improving the quality of life of patients, also it has potential to improve nerve trauma-induced neuropathy. Hence, it can be used as better treatment option in NP to give patient compliance. This effect may be due to its potent antioxidant and anti-inflammatory activity. Further studies are required to determine the exact molecular mechanism of action of EP.
| Acknowledgment|| |
The authors are grateful to Department of Pharmacology, AISSMS College of Pharmacy Pune for supporting this study and providing technical facilities for the work. The authors are also thankful to Dr. Ashwini R. Madgulkar, Principal of AISSMS College of Pharmacy Pune for valuable guidance and support.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
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