|Year : 2016 | Volume
| Issue : 3 | Page : 440-448
Statins attenuate hyperalgesia and inflammation in experimentally induced acute and neuropathic pain in rats
Elsayed M Kamel1, Ahmed F Elsaid2, Eid A Gumaa3, Abd Elhafez M El Sheweal4
1 Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Community Medicine and Public Health, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Zagazig University, Zagazig, Egypt
4 Department of General Surgery, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||12-Sep-2015|
|Date of Acceptance||11-Mar-2016|
|Date of Web Publication||31-Aug-2016|
Eid A Gumaa
Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Zagazig University, Zagazig City, Sharkia
Source of Support: None, Conflict of Interest: None
Available medications for the treatment of neuropathic pain, such as steroidal anti-inflammatory drugs and NSAIDs, were shown to be of limited therapeutic benefit.
This study aimed to evaluate the analgesic and anti-inflammatory effects of atorvastatin and pravastatin in acute and neuropathic pain in rats.
Materials and methods
Acute and neuropathic pains were induced in rat models by means of subplantar carrageenan injection and partial sciatic nerve ligation (PSNL), respectively. The anti-inflammatory effect of statins was assessed by the reduction in plantar edema (at 0, 1, 2, and 3 h) and prolongation of paw withdrawal reaction time in response to thermal stimulation (at 0, 0.5, 1, 2, 3, and 4 h) after carrageenan injection. Atorvastatin (2, 4, or 8 mg/kg) and pravastatin (4, 8, or 12 mg/kg) were administered intraperitoneally 30 min before carrageenan injection. The effect of statins on neuropathic pain was assessed by prolongation of paw withdrawal reaction time in response to thermal stimulation evaluated at 0, 3, 6, 9, 12, 15, and 18 days after PSNL. Atorvastatin (2, 4, or 8 mg/kg) and pravastatin (4, 8, or 12 mg/kg) were administered orally for 18 consecutive days after PSNL. In addition, the effect of atorvastatin and pravastatin on total cholesterol and tumor necrosis factor-α levels was also assessed.
Both atorvastatin and pravastatin ameliorated carrageenan-induced rat paw edema and prolonged withdrawal time in response to thermal-induced pain. Both statins were also effective in ameliorating neuropathic pain induced by PSNL. These effects were independent of statin-induced hypolipidemic action but were concomitant with reduction of serum tumor necrosis factor-α levels.
Atorvastatin and pravastatin demonstrated effective therapeutic potentials to reduce acute and chronic pain together with the associated inflammation and hyperalgesia independent of their hypolipidemic effect.
Keywords: hyperalgesia, inflammation, neuropathic pain, statins
|How to cite this article:|
Kamel EM, Elsaid AF, Gumaa EA, El Sheweal AM. Statins attenuate hyperalgesia and inflammation in experimentally induced acute and neuropathic pain in rats. Ain-Shams J Anaesthesiol 2016;9:440-8
|How to cite this URL:|
Kamel EM, Elsaid AF, Gumaa EA, El Sheweal AM. Statins attenuate hyperalgesia and inflammation in experimentally induced acute and neuropathic pain in rats. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 May 9];9:440-8. Available from: http://www.asja.eg.net/text.asp?2016/9/3/440/189562
| Introduction|| |
Statins are a group of drugs that lower plasma cholesterol level by inhibiting 3-hydroxy-3-methyl-glutaryl-co-enzyme A (HMG-CoA) reductase, which is the rate-limiting step of cholesterol biosynthesis . Most clinical trials on statins reported a significant reduction in the relative risk for coronary events, which constitutes the major cause of death in the USA, versus placebo . Therefore, statins’ prescription has been central in the treatment of dyslipidemia and in the primary and secondary prevention of coronary heart disease . Several studies demonstrated that the pharmacological actions of statins are not limited to the well-known lipid lowering action but extend to produce several effects, which had been termed statin pleiotropic effects . Some of the discovered nonlipid lowering, pleiotropic effects of statins involve improving endothelial function, decreasing oxidative stress and inflammation, enhancing the stability of atherosclerotic plaques, and inhibiting the thrombogenic response . Furthermore, statins have demonstrated a beneficial effect on the immune system, central nervous system, and bone .
Chronic (neuropathic) pain is a common complaint in clinical practice, and is defined as the pain that continues beyond the usual recovery period from an injury or illness, or that lasts for months or years due to a chronic condition . In the USA, it has been reported that one in every three Americans had experienced a lifetime incidence of chronic pain . In Europe, the prevalence of chronic pain was around 25–30% . It has been proposed that the cause of chronic pain could be attributed to neuropathic pain in around one-fifth of cases ,. Neuropathic pain includes a heterogeneous group of disorders that are caused by lesions or diseases affecting parts of the nervous system, which normally signal pain . Causes of neuropathic pain include traumatic, ischemic, and inflammatory lesions. One explanation for the high prevalence rate of chronic and neuropathic pain is the absence of effective treatments . In addition, neuropathic pain tends to be more refractory compared with the non-neuropathic one to conventional analgesics, such as NSAIDs and opioids . Chronic neuropathic pain greatly reduces the physical and the emotional capacity and the quality of life of affected individuals. Pain-induced disability, absenteeism, and investigative and therapeutic needs, all impose substantial economic cost to the affected individuals, their families, and the whole society .
One mechanism by which peripheral nerve injury produces neuropathic pain is by inducing hyperexcitability of the spinal cord dorsal horn neurons . Recruitment of macrophages to the site of nerve injury releases proinflammatory cytokines that contribute to hyperexcitability ,. In addition, after peripheral nerve injury, microglia cells that surround spinal cord neurons are converted to an active form where cell receptor expression, intracellular signaling, and inflammatory mediators are released and contribute to the hyperexcitability of the dorsal horn neurons .
There is increasing evidence indicating the benefit of statins therapy in the treatment of neuropathic pain. Many of the pleiotropic therapeutic potentials of statins make them a possible candidate as a treatment or an adjuvant to the ordinary steroidal anti-inflammatory analgesics and NSAIDs for the treatment of neuropathic pain. Therefore, this work was designed to investigate the possible analgesic and anti-inflammatory effects of statins in acute and neuropathic painful conditions.
| Materials and methods|| |
Drugs and chemicals
Carrageenan powder (Sigma, St Louis, Missouri, USA) was suspended in saline. Atorvastatin powder (Pfizer, Cairo, Egypt) was dissolved in phosphate-buffered saline. Pravastatin powder (Bristol-Myer Squibb, Cairo, Egypt) was dissolved in saline. Thiopental powder (EPICO, 10th of Ramadan, Egypt) was dissolved in saline.
Sixty-four male albino rats weighing 150–170 g were utilized in this study. The animals were kept at a constant temperature (23±2°C), humidity (60±10%), and a light/dark (12/12 h) cycle. Food and water were allowed ad libitum. Experimental design and animal handling were approved by the local authorities at the Faculty of Medicine, Zagazig University, Egypt (Ethical Committee for Animal Handling at Zagazig University).
Thirty-two rats were used for the acute study and were divided into eight equal groups (four rats each) as follows:
Group 1 rats received 0.05 ml/kg normal saline administered through the subplantar route and served as controls.
Group 2 (the carrageenan-treated group) rats received subplantar injection of 0.05 ml of 1% carrageenan dissolved in saline.
Groups 3–5 (the atorvastatin-pretreated groups) received intraperitoneal injection of atorvastatin at doses of 2, 4, or 8 mg/kg, respectively, 30 min before carrageenan injection.
Groups 6–8 (the pravastatin-pretreated groups) received intraperitoneal injection of pravastatin at doses of 4, 8, or 12 mg/kg, respectively, 30 min before carrageenan injection.
Thirty-two rats were used for the chronic study and were divided into eight equal groups (four rats each) as follows:
Group 1 included sham-operated rats in which the sciatic nerve was exposed without ligation.
Group 2 included rats subjected to partial sciatic nerve ligation (PSNL).
Groups 3–5 (the atorvastatin-pretreated groups) received atorvastatin orally by means of gavage at doses of 2, 4, or 8 mg/kg, respectively, for 18 consecutive days after (PSNL).
Groups 6–8 (the pravastatin-pretreated groups) received pravastatin orally by means of gavage at doses of 4, 8, or 12 mg/kg, respectively, for 18 consecutive days after (PSNL).
In this study, the doses of statins (2–12 mg/kg/day) were selected according to the available data in the literature for in-vivo studies of statins in other experimental models in rodents , and according to our own data.
The acute anti-inflammatory effect of atorvastatin and pravastatin was investigated by using the carrageenan-induced edema test in which rats were given 0.05 ml of 1% carrageenan suspended in saline by means of subplantar injection in its right back paw . The diameter of the induced edema was measured in millimeter using an instrument called ‘pawkolis’ before and after statin injection every hour for 4 h.
The analgesic effect of atorvastatin and pravastatin in neuropathic pain was evaluated in the PSNL rat model as described by Seltzer et al. . The rats were anesthetized with intraperitoneal thiopental 25 mg/kg  and kept under aseptic condition with intramuscular injection of ceftriaxone 18 mg/kg. The left sciatic nerve was exposed at high thigh level. The dorsum of the nerve was carefully freed from surrounding connective tissue at a site near the trochanter just distal to the point at which the posterior biceps semitendinosus branches off the common sciatic nerve. A 6/0 silk suture was inserted into the nerve with a 3/8 curved, reversed cutting needle and tightly ligated so that the dorsal third of the nerve thickness was trapped in the ligature. The wound was then closed with a muscle suture (4/0) and 2–3 skin sutures (4/0).
Thermal stimulation and measurement of paw withdrawal reaction time: the induced hyperalgesia in rats either by injecting carrageenan or by means of PSNL was measured using the paw withdrawal reaction time. Pain was induced using the IITC model 390 Paw Stimulator Analgesia Meter (IITC Inc. Life Science, Woodland Hills, CA, USA) as described by Lanher’s et al. . This instrument allows the user to apply thermal stimulation to the rats with controlled intensity and brightness without any physical contact between the test subject and the thermal source.
Serum cholesterol and tumor necrosis factor-α (TNF-α) assay: blood samples were collected from PSNL rats through the retrobulbar route at the end of the experiments. Blood was allowed to coagulate at room temperature for 20 min and was then centrifuged at 3000 rpm for 6 min. Cholesterol level was assessed with the Amplex Red Cholesterol Assay Kit (Catalog no. A12216, Molecular Probes, Inc., Eugene, OR 97402, USA) according to the manufacturer’s instructions.
Plasma levels of TNF-α were measured with a commercial enzyme-linked immunosorbent assay kit (R&D System, Minneapolis, Minnesota, USA) following the instructions of the manufacturer. The TNF-α concentration was measured spectrophtometrically at a wavelength of 450 nm. The concentration of TNF-α was calculated by comparing the optical density of the samples with the standard curve.
All data were presented as mean±SEM. Comparison between groups was determined using mixed-type analysis of variance . The criterion for statistical significance was P less than 0.05. statistical package for social science for windows 7, version 14 (SPSS Inc., Chicago, Illinois, USA) and Microsoft Excel 2013 were used for the analysis.
Animal sample size was estimated based on pilot studies conducted in our laboratory, which suggested that atorvastatin and pravastatin could increase reaction time and reduce the diameter of carrageenan-induced edema with an effect size of 50 and 40%, respectively. In the PSNL rat model, atorvastatin and pravastatin showed increased reaction time with an effect size of around three folds for both compounds. Therefore, an effect size of 40% reduction in carrageenan-induced edema constituted the most conserved statin-induced effect size and was used to estimate the required sample size. For repeated-measure analysis of variance with at least four repeated measurements in eight different groups and at 0.05 α level of significance, a sample size of 32 animals was found to achieve 95% power to significantly detect an effect size change of 40% for each compound. Sample size calculation was performed using G*Power software package, version 188.8.131.52 (G*Power Software, Franz Faul, Germany).
| Results|| |
Effects of subplantar injection of carrageenan and PSNL on rat paw hyperalgesia and edema.
Injection of carrageenan (0.05 ml of 1% solution) induced significant inflammatory hyperalgesia and edema compared with the saline injected group. This was demonstrated by a significant (P<0.05) reduction in the paw withdrawal reaction time in response to thermal stimulation and a significant increase in the subplantar edema compared with the control group at all measurement time points [Table 1], [Table 2], [Table 3], [Table 4]. Similarly, PSNL resulted in a sharp decrease in reaction time compared with the sham group ([Table 5] and [Table 6]). Notably, PSNL did not induce similar response in the contralateral limb as evidenced by the normal reaction time to the same thermal stimulus.
|Table 1 Effect of pretreatment with atorvastatin (2, 4, and 8 mg/kg, intraperitoneally) on paw withdrawal reaction time in response to a thermal stimulus after induction of carrageenan-induced paw inflammation|
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|Table 2 Effect of pretreatment with atorvastatin (2, 4, and 8 mg/kg, intraperitoneally) on the diameter of carrageenan-induced paw inflammation (edema) and percent change|
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|Table 3 Effect of pretreatment with pravastatin (4, 8, and 12 mg/kg, intraperitoneally) on reaction time to a thermal stimulus of carrageenan-induced paw inflammation (n=4)|
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|Table 4 Effect of pretreatment with pravastatin (4, 8, and 12 mg/kg, intraperitoneally) on diameter of carrageenan-induced paw inflammation (edema) and percent change|
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|Table 5 Effect of pretreatment with atorvastatin (2, 4 and 8 mg/kg/day) orally for 18 days on paw withdrawal reaction time after partial sciatic nerve ligation|
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|Table 6 Effect of pretreatment with pravastatin (4, 8, and 12 mg/kg/day) orally for 18 days on paw withdrawal reaction time after partial sciatic nerve|
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Effect of prior administration of atorvastatin on paw withdrawal reaction time after carrageenan-induced hyperalgesia [Table 1].
Administration of atorvastatin 2 mg/kg 30 min before carrageenan failed to produce any change in the reaction time to thermal stimulus at all time points of measurements. However, on increasing the dose of atorvastatin to 4 mg/kg, it produced a significant (P<0.05) prolongation in the reaction time compared with controls at all time points of measurements. Further increase in the dose of atorvastatin to 8 mg/kg produced a significant (P<0.05) prolongation in reaction time of the hind paw compared with controls at all time points of measurements. The dose of 8 mg/kg atorvastatin produced more significant prolongation in paw withdrawal reaction time compared with 4 mg/kg atorvastatin at all measured time points. This result demonstrated that atorvastatin prolonged the reaction time in a dose-dependent manner.
Effect of prior administration of atorvastatin on the diameter of carrageenan-induced edema of rat paw [Table 2].
The results of the present study demonstrated that intraperitoneal administration of atorvastatin 2 mg/kg 30 min before carrageenan (0.05 ml of 1%) administered by means of subplantar injection in the right back paw did not produce significant changes in the diameter of paw edema after 0.5 and 1 h. However, a significant (P<0.05) reduction in the diameter of paw edema was observed after 2, 3, and 4 h compared with the carrageenan group. Increasing the dose of atorvastatin to 4 or 8 mg/kg resulted in significant (P<0.05) decrements in the paw edema induced by carrageenan compared with the carrageenan only group when the diameter was measured after 0.5, 1, 2, 3, and 4 h. It was noticed that atorvastatin produced a significant (P<0.05) reduction in carrageenan-induced paw edema in a dose-dependent manner.
Effect of prior administration of pravastatin on paw withdrawal reaction time after carrageenan-induced hyperalgesia [Table 3].
The results of the current work demonstrated that intraperitoneal administration of pravastatin 4, 8, and 12 mg/kg produced significant (P<0.05) prolongation in the reaction time in response to thermal stimulation in the pravastatin-treated group compared with the carrageenan-treated one at 3 h measurement. Further increase of pravastatin dose to 8 and 12 mg/kg resulted in significant (P<0.05) prolongation in the reaction time compared with the carrageenan-treated group. The prolongation in the reaction time that was induced by pravastatin was in a dose-dependent manner.
Effect of prior administration of pravastatin on the diameter of carrageenan-induced edema of rat paw [Table 4].
The results of the present study showed that pravastatin 4 mg/kg administered 30 min before carrageenan (0.05 ml of 0.1%) resulted in a significant (P<0.05) reduction in the diameter of the inflammatory edema induced by carrageenan in the rat paw compared with the carrageenan-treated group at 2, 3, and 4 h. Increasing pravastatin to 8 mg/kg produced a significant (P<0.05) decrease in the diameter of the paw edema compared with the carrageenan-treated group. Further increase in the dose of pravastatin to 12 mg/kg produced a significant reduction in the carrageenan-induced inflammatory edema compared with the carrageenan-treated group at all time points of measurements. Notably, the significant reduction in the inflammatory edema that was observed with pravastatin was in a dose-dependent manner despite it not being a time-dependent one. The recorded reductions at all points of measurements showed a significant reduction between the different doses at different time points (1, 2, and 3 h).
Effect of daily administration of atorvastatin and pravastatin on paw withdrawal (reaction time) after PSNL ([Table 5] and [Table 6]).
The results of the present work showed that daily administration of atorvastatin 2 mg/kg orally for 18 consecutive days produced significant (P<0.05) prolongation in the withdrawal (reaction) time at all times of measurements (3, 6, 9, 12, 15, and 18 days) compared with controls. Increasing the dose of atorvastatin to 4 and 8 mg/kg also produced significant (P<0.05) prolongation in the reaction time to thermal stimulation at all times of measurement, denoting that the analgesic effect of atorvastatin is in a dose-dependent manner. It was noted that the significant prolongation in latency was dose dependent and time dependent. Similarly, pravastatin at 4, 8, and 12 mg/kg for 18 consecutive days produced a significant prolongation in latency of PSNL rats compared with controls. It was also noticed that the significant prolongation in the latency to thermal stimulation was both dose dependent and time dependent.
Effect of daily administration of atorvastatin and pravastatin orally for 18 days on serum cholesterol and TNF-α in PSNL rats [Figure 1], [Figure 2], [Figure 3], [Figure 4].
|Figure 1 Serum cholesterol levels of atorvastatin-treated rats were not significantly reduced compared with sham at all studied doses and time points. PSNL, partial sciatic nerve ligation.|
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|Figure 2 Serum cholesterol levels of pravastatin-treated rats were not significantly reduced compared with sham at all studied doses and time points. PSNL, partial sciatic nerve ligation.|
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|Figure 3 Serum TNF-α level of atorvastatin-treated PSNL rats was significantly reduced compared with the nontreated PSNL at 4 and 8 mg/kg doses and at all studied time points. PSNL, partial sciatic nerve ligation; TNF-α, tumor necrosis factor-α.|
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|Figure 4 Serum TNF-α level of pravastatin-treated PSNL rats was significantly reduced compared with the nontreated PSNL. At a dose of 12 mg/kg, the reduction was observed at all studied time points. At a dose of 8 mg/kg, the reduction was observed at 12 and 18 days only. PSNL, partial sciatic nerve ligation; TNF-α, tumor necrosis factor-α.|
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The results of the present work revealed that neither atorvastatin nor pravastatin produced any significant changes in serum cholesterol levels in both the control or treated PSNL groups at different times of measurements (6, 12, and 18 days). Meanwhile, there was a significant (P<0.05) elevation in TNF-α in the PSNL group compared with the control group. Administration of atorvastatin 2 mg/kg or pravastatin 4 mg/kg did not significantly affect TNF-α levels compared with PSNL at all times of measurements. Further increasing the dose of atorvastatin to 4 and 8 mg/kg resulted in significantly (P<0.05) reduced TNF-α levels at all times of measurements. Notably, 8 mg/kg of atorvastatin completely reversed TNF-α to the level of the control group. Similarly, administration of pravastatin 8 mg/kg resulted in significantly (P<0.05) reduced TNF-α at 12 and 18 days only, whereas 12 mg/kg produced a significant reduction at 6, 12, and 18 days.
| Discussion|| |
Statins were found to possess a large spectrum of pleiotropic effects that seem to be unrelated to their hypocholesterolemic effect such as their anti-inflammatory and immunomodulatory actions ,. Therefore, the objective of the present work was to investigate the analgesic and the anti-inflammatory effects of some statins on acute and chronic painful conditions. The carrageenan-induced inflammation and PSNL rat models were made to elicit acute and chronic pain conditions, respectively.
It was evident from the results of the present study that prior administration of atorvastatin and pravastatin has largely attenuated carrageenan-induced and PSNL-induced acute and chronic hyperalgesia, respectively. The analgesic effect of atorvastatin and pravastatin against acute and chronic hyperalgesia was observed in a dose-dependent manner. In parallel, administration of atorvastatin and pravastatin was associated with a significant anti-inflammatory effect that was evidenced by reduction in the diameter of carrageenan-induced inflammatory edema in the rat paws. The anti-inflammatory effect of statins was observed when administered either before carrageenan or immediately after PSNL and lasted as long as the drug was present. Similar results were demonstrated by Davis et al. , who reported that statins could ameliorate the neuropathic pain and relieve the associated inflammatory edema.
Atorvastatin and pravastatin were chosen in this work because of their widely different pharmacokinetic and pharmacodynamic properties. Pravastatin has a relatively long half-life, whereas atorvastatin has a shorter one . In addition, atorvastatin and pravastatin differ in their lipophilicity; atorvastatin is relatively lipophilic compared with pravastatin, which is hydrophilic . This is a significant distinction because atorvastatin can pass the blood–brain barrier readily, whereas pravastatin relatively cannot pass under normal conditions . In case of peripheral nerve injury, as in the current work, the blood–spinal cord barrier is compromised . Therefore, after PSNL, it is plausible to propose that hydrophilic statins like pravastatin could gain direct access to the brain. This is based on the reported differences between pravastatin and atorvastatin. Pravastatin has been reported to have a greater potency both in inhibiting the HMG-CoA reducatase enzyme and reducing low-density lipotprtein cholesterol levels compared to atorvastatin ,.
The comparable results obtained from both atorvastatin (lipophilic) and pravastatin (hydrophilic) in the present work suggested a drug class effect of the statin family to relieve inflammation and hyperalgesia of acute or neuropathic pains. Atorvastatin seems to be more efficient compared with pravastatin in diminishing thermal hypersensitivity at all tested doses. This finding was contradictory to that of Echeverry et al. , who reported that pravastatin was more potent compared with atorvastatin in alleviating neuropathic pain induced by nerve injury. This difference could be attributed to differences in the species of the utilized animal; rats were used in our study, whereas mice were used in the study of Echeverry et al. . Further investigations on whether the difference in drug efficacy is related to lipophilicity, permeability to the blood–brain barrier, differences in half-lives, potency at lowering low-density lipoprotein cholesterol, or another property are needed because it is not clear.
As regards the anti-inflammatory effect of statins, it is evident from the results of the present study that statins could modulate inflammatory-associated cytokine profile. In the current work, a significant reduction in TNF-α after treatment with both atorvastatin and pravastatin was recorded. This result is in agreement with the previously reported statin-induced reduction of TNF-α in different biological systems such as cell culture, animals, and humans ,,. TNF-α is an important pain modulator because intraplantar injection of TNF-α into the rat’s paw was shown to induce inflammatory hyperalgesia . It is possible that the ability of statins to reduce cytokine expression in the periphery could play a role in their ability to ameliorate the neuropathic pain ,,.
An important finding of the current study was that statin-induced attenuation of PSNL-induced neuropathic pain and carrageenan-induced hyperalgesia and inflammation was independent of their hypolipidemic effect. This was evidenced by the normal cholesterol levels in all rat groups treated with atorvastatin or pravastatin. Failure of statins in reducing cholesterol level at all used doses was reported in our study, which is in agreement with the results obtained from several previous studies in mice and rats ,. For example, mice treated with 10 mg/kg daily of rosuvastatin for 3 days in a rat model of transient cerebral ischemia did not show any reduction in blood cholesterol level. Similarly, administration of atorvastatin 10 mg/kg daily for 20 weeks in lupus erythematosus rat model showed no reduction in serum cholesterol . One explanation for this phenomenon in rodents is the observed upregulation of HMG-CoA reductase enzyme that occurs after administration of statins . This phenomenon was not reported in humans and other primates, making comparison of effective statin dose difficult to compare between the two species .
| Conclusion|| |
The results of the present study demonstrated a therapeutic potential of statins as anti-inflammatory and analgesic agents. The present study suggests that statins might be administered shortly after nerve injury to prevent progression to neuropathic pain. It should be noted that common side effects associated with statins are not expected to occur with a low dose of statins expected to produce analgesic and anti-inflammatory effects. Further clinical and experimental studies are required to confirm the present findings and to give more clarification about the role of statins in protecting against neuropathic pain.
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Conflicts of interest
All authors declare no conflict of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]