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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 34-39

The analgesic effect of metformin on paclitaxel-induced neuropathic pain model in rats: By considering pathological results


1 Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
2 Department of Pharmacology and Toxicology, Veterinary medicine, Atatürk University, Erzurum, Turkey
3 Department of Medical Services and Techniques, Vocational School of Health Services, Bayburt University, Bayburt, Turkey
4 Department of Pathology, Faculty of Medicine, Atatürk University, Erzurum, Turkey

Date of Submission30-Dec-2016
Date of Decision01-Oct-2017
Date of Acceptance25-Feb-2018
Date of Web Publication24-Oct-2018

Correspondence Address:
Maryam Mohammadzadeh
Department of Medical Pharmacology, Faculty of Medicine, Ataturk University, Erzurum
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1455_16

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 > Abstract 


Background and Objective: Metformin (MET) has been used as an antidiabetic agent for type II diabetes. At the same time, recent researches have shown that the clinical improvement of MET is useful for nerve damage. In this study, we investigated the analgesic effect of MET in paclitaxel (PAC)-induced neuropathic pain.
Materials and Methods: Forty-two adult, female rats, Wistar strain weighing 220 ± 10 g were randomly divided into 5 experimental groups. PAC was intraperitoneally (IP) administered (2.0 mg/kg) for 4 groups every other day (0, 2, 4, and 6 days). By the 30th day, MET (100, 200, and 400 mg/kg) was administered to 4 groups. Before and after treatment, basal pain threshold values were measured with Randall–Selitto analgesiometer test. At the end of experiment, pathological values were measured in selected regions including brain (motor cortex, M1), spinal cord (L4-L5), sciatic nerve, and muscle.
Results: According to our results, PAC-induced neuropathic pain reached to highest level at 14th day. Four hundred milligram/kilogram concentration of MET remarkably decreased PAC-induced neuropathic pain. On the other hand, pathologic features have shown that PAC had significant pathological change in the brain and spinal cord while in the peripheral nerves and muscles had not shown any pathological change.
Conclusion: The pathological results of the current study for the first time demonstrated that MET beside of its antidiabetic effects reversed neuropathic pain induced by PAC. Consequently, this research can be promising for cancer patients that suffering from neuropathic pain induced by anticancer drugs.

Keywords: Metformin, neuropathic pain, paclitaxel, Randall–Selitto analgesiometer test


How to cite this article:
Hacimuftuoglu A, Mohammadzadeh M, Taghizadehghalehjoughi A, Taspinar N, Togar B, Nalcı KA, Okkay U, Gundogdu B. The analgesic effect of metformin on paclitaxel-induced neuropathic pain model in rats: By considering pathological results. J Can Res Ther 2020;16:34-9

How to cite this URL:
Hacimuftuoglu A, Mohammadzadeh M, Taghizadehghalehjoughi A, Taspinar N, Togar B, Nalcı KA, Okkay U, Gundogdu B. The analgesic effect of metformin on paclitaxel-induced neuropathic pain model in rats: By considering pathological results. J Can Res Ther [serial online] 2020 [cited 2020 Jun 6];16:34-9. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/34/243486




 > Introduction Top


Taxanes are a significant class of antitumor drugs that were defined in 1966 and pure form of taxane was obtained from Taxus brevifolia in 1969; however, their structures were published in 1971.[1] Paclitaxel (PAC) is an important and effective agent of taxane group which is widely used as a chemotherapeutic drug,[2] in cancer diseases such as ovarian,[3] nonsmall cell lung cancer,[4] gastric,[5] breast,[6] and colon.[7] In addition, researchers found that PAC has some features which make it an agent for local drug therapy of excessive arterial smooth muscle cell proliferation in restenosis after balloon angioplasty or stent implantation.[8],[9],[10],[11] PAC is an antimicrotubule factor which inhibits tumor cell division in both G2/M and G0/G2 phases by its action on microtubule mounting. In spite of these good efficacies, PAC has some side effects including hypersensitivity reactions, cardiotoxicity, arthralgias, myalgias, neutropenia, central, and peripheral neuropathy.[12],[13],[14],[15],[16],[17],[18] On the other hand, metformin (MET) is a biguanide compound antidiabetic that has been widely used nearly a century for treatment of type 2 diabetes which activates adenosine monophosphate-activated protein kinase (AMPK).[19],[20],[21] MET reduces hyperglycemia but does not induce hypoglycemia. Its effects are made outside the pancreas, do not affect beta cells and do not increase insulin secretion. It acts mainly through three mechanisms: (i) It increases the use of glucose by accelerating anaerobic glycolysis and it causes elevated lactic acid levels. (ii) It reduces intestinal glucose absorption. (iii) It decreases gluconeogenesis.[22] MET was also found to be beneficial in patients with obesity and polycystic ovary syndrome. Preclinical and clinical studies shown that MET has an antitumor effect on cancer cells and reduced cancer-associated inflammatory response.[23]

Neuropathy and/or neuropathic pain is caused by damage to the peripheral and central nervous system that is produced by multiple etiologies, including physical trauma, metabolic diseases, viral infections, nerve compression, and chemotherapy.[24],[25],[26],[27] Neuropathic pain that is caused by chemotherapy agents is the most common neurological difficulty which leads to dose limiting for many chemotherapeutic drugs.[28],[29] Notwithstanding, antiepileptic, antidepressant, and antidiabetic drugs were used for treatment and control in patients with chemotherapy-induced neuropathic pain; at present, no impressive drug is available for treatment.[30],[31],[32]

New researchers demonstrate that MET prevents mechanical allodynia in models of neuropathic pain induced by spinal nerve ligation in rats.[33] However, the effects of MET on PAC-induced neuropathic pain have not been investigated. In this research, analgesic effect of MET in neuropathic pain induced by PAC was investigated by Randall–Selitto test. At the same time, we investigated pathological scoring results.


 > Materials and Methods Top


Chemicals

In this study, PAC (6 mg/mL Taxol®) was obtained from Corden Pharma Latina S.P.A. (Latina, Italy). MET (Glifor® 1000 mg film-coated tablets) was obtained from Pharmavision (Istanbul).

Animals

This study was managed at the Medical Experimental Research Center in Ataturk University (Erzurum, Turkey). The ethical committee of Ataturk University confirmed the study protocol (42190979-11/153). In this experiment, we used 40 female albino Wistar rats weight 200 ± 10 g. Animals were maintained under controlled light cycle (12/12 h) and temperature (22°C ± 2°C) ad libitum . The principle support the well-being of animals used for scientific goals, and purpose to reduce their experience of pain and distress.

Paclitaxel-induced neuropathic pain model in rats

The Randall–Selitto analgesiometer test is a method for measurement of the pain response in animals. It is used in basic pain research which test the efficacy of analgesic by observing the reaction to progressively increasing pressure on hind paw.[34] Pain is assumed to be present if the animal starts to show the effort or flight response. Based on the previously performed tests by Randall and Selitto after induction of neuropathic pain, the nociceptive threshold was measured with an analgesiometer (Ugo Basile, Italy).[35] The animals were randomly divided into five equal groups ( n = 8). Pain threshold for referred pain was measured on Randall–Selitto analgesiometer just before and after drug administration. After measuring the baseline of pain sensitivities by Randall–Selitto analgesiometer, four groups of rats were IP injected every other day (days 0, 2, 4, and 6) with PAC (2.0 mg/kg) in order to measure mechanical hyperalgesia and allodynia. Since PAC-induced allodynia reached peak severity on 28th day, 100, 200, and 400 mg/kg concentrations of MET were given successively for 14 consecutive days. 1 ml distilled water IP were given to control group.

Pathology

The rats were sacrificed under deep anesthesia. The brain, sciatic nerve, spinal cord, and the muscle tissue were removed and fixed for 24 h in 10%-buffered formaldehyde. The processed all tissues dehydrated through and processed by graded alcohols (Sigma Chemical Comp., St. Louis, MO, USA) and xylene (Sigma Chemical Comp., St. Louis, MO, USA). Then, immersed in paraffin series and embedded in fresh paraffin (Merck, Darmstadt, Germany), and then, 0.5 μm sections were obtained through Leica (2450, Turkey) microtome device. For the microscopic examination of sections were used hematoxylin and eosin stain. The slides were covered, and photographs were taken using a light microscope with a camera attachment (Nikon Eclipse E600, Japan). Finally, all tissue samples examined under a microscope and were done by scorings: 0, no damage; 1, slight damage; 2, moderate damage; and 3, represent severe damage.[36]

Neuronal cell counting

Cell counting test was used to determine the number of neuronal cells that was described by Smits et al .[37] For this experiment, we used Leica DM 4000b microscope, Leica DFC295 digital color video camera, and stereo investigator software (version 9). This setup has the option of demarcating a scoring area on the slide, in which the software selects random 3 different fields (DFs). The central areas of these DFs were used for visually counting neuronal cells (Purkinje). These cells were marked manually and counted using the software.

Statistical analysis

The statistical analyses were performed by one-way analysis of variance using the SPSS version 20.0 software (Chicago, IL, USA). P < 0.05 was considered as statistically significant difference for all tests.


 > Results Top


PAC-induced neuropathic pain model is shown in [Figure 1]. Before the PAC injection to be done, on different days, allodynia was measured by Randall–Selitto analgesiometer testing equipment, by applying pressure to the hind paw of all the animals. Pain thresholds were measured after PAC was injected to rats four times in total (days 0, 2, 4, and 6) with one-day interval. PAC-evoked pain was not observed until 14th day. On 14th day, there was a meaningful threshold decrease observed. The findings of the present study clearly showed that there was a significant difference between the control groups and the PAC-administered groups in terms of pain occurrence.
Figure 1: Pain threshold values in 0th day and after administration PAC in 7th, 14th, and 21st days. PAC: Paclitaxel; Pain, according to the results of control, ** P < 0.0001

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In this study, 28 days after PAC injection, neuropathic pain has reached the most severe levels. After 2 days, MET was used for treatment at three different concentrations (100, 200, and 400 mg/kg) 14 consecutive days. to [Figure 2], considering measurement values (37, 44, and 51 days), there was no significant change about pain threshold of PAC as compared with control group ( P > 0.05). In addition, low concentration of MET (100 mg/kg) did not show any analgesic effect as compared with the control group. 200 mg/kg concentration of MET exhibited the remarkable analgesic effect on the 51st day while 400 mg/kg concentration of MET exhibited the remarkable analgesic effect both 44th and 51st days.
Figure 2: Pain threshold values in control, PAC, and 30th–43rd day after administration MET. PAC: Paclitaxel, MET: Metformin, Pain, according to the results of 30th day–51st day ** P < 0.0001, * P < 0.05

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Cell count test is applied on medulla spinalis (MS) and motor cortex (MC) cross-sectional area [Figure 3]. By considering our conclusion, results are consistent with the data model of pain. According to cell count results, the PAC group showed a substantial decrease in cell populations on MS and MC cross-sectional areas ( P < 0.0001). In addition, 100 and 200 mg/kg concentrations of MET indicated a significant decrease in the MS area, as compared with the control group ( P < 0.05) [Table 1]. However, 200 mg/kg concentration of MET had more neuroprotective effects in MS area than MC area. On the other hand, 400 mg/kg concentration of MET showed neuroprotective effect both MS and MC areas [Table 2]. In other words, 400 mg/kg concentration of MET decreased PAC-induced toxicity on both areas.
Figure 3: The cell count of medulla spinalis and cortex. PAC: Paclitaxel, MET: Metformin, according to the results of pathology ** P < 0.0001, * P < 0.05

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Table 1: The histopathological examination of medulla spinalis

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Table 2: The histopathological examination of cortex

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 > Discussion Top


The National Comprehensive Cancer Network Guidelines propose that taxanes such as for the treatment solid tumors PAC.[36],[37] PAC is a very common anticancer agent which leads to some adverse effects in cancer patients that among them, neuropathic pain is severe form of symptoms in cancer patients.[12],[13] Neuropathic pain is usual and dose-related adverse effect of chemotherapeutic drugs that has a major influence on quality of life.[38] Oncologists tend to reduce the dose of PAC because in patients with this type of pain, there are not any effective painkiller.[39]

The purpose of the present study was to identify the analgesic effect of MET against PAC-induced neuropathic pain in rat models. Furthermore, for the first time, histological techniques were used for confirming the protective effect of MET on brain, spinal cord, sciatic nerve, and muscle. In some preclinical activities, MET has shown antitumor effect, and at the same time, cancer-associated inflammatory response decreased on cancer cells.[40] Melemedjian et al .[41] demonstrated that MET relieves pain amplification which takes place in response to peripheral nerve injury in rats and mice. In other study, Mao-Ying et al .[33] demonstrated that MET (200 mg/kg) protects against PAC and cisplatin-induced neuropathic pain in mouse model which was measured by using von Frey test.

In addition, some studies reported that PAC caused loss of epidermal nerve fibers.[42] It was understood that after loss of epidermal nerve fibers, it caused partial loss of the sense of mechanical origin.[42] Administration of MET (200 mg/kg i.p.) alongside with chemotherapy is thought to prevent the formation of these sensory deficits.[33] Because of these reasons, we have chosen MET as a treatment drug in our study. In our study, according to measurement values (37, 44, and 51 days), it was indicated that 200 and 400 mg/kg of MET decreased PAC-induced allodynia. In this experiment, when we compared all groups with control group, 200 mg/kg concentration of MET showed reduction in neuropathic pain. According to our results, neuropathic pain in 37th day decreased by 33%, in 44th day decreased 43%, and in 51th day decreased 61%. Likewise, 400 mg/kg concentration of MET showed significant reduction in neuropathic pain in 37th day decreased by 38%, 44th day decreased 67%, and 51st day decreased 80%. These results suggested that the therapeutic effect depends on time and the concentration of MET.

In the present study, brain, spinal cord, peripheral nerves, and muscles were removed for histopathological examination. According to our histopathological study, in peripheral nerves and muscles, we did not observe any pathological findings while in the brain and spinal cord had been observed significant pathological results in the PAC group. After administration all concentrations of MET, pathologic scores in the spinal cord more improved and 400 mg/kg concentration of MET was meaningful. As a result, considering all concentrations, 400 mg/kg concentration of MET turned back both neuropathy and pathological damage in spinal cord. While 200 mg/kg concentration of MET was only reversed the allodynia.

Conventionally, there are differences between nerve ligation model and neuropathic pain induced by chemotherapeutic drugs. The benefits of AMPK activation in models of neuropathy induced by trauma may be associated with reduction of mTOR and MAPK signaling.[30] However, about neuropathic pain induced by chemotherapeutics, there is no clear information on the change of these pathways. However, it was determined in neuropathic pain induced by chemotherapeutic drugs; there are significant changes in mitochondrial function which is important in AMPK activation. Mitochondria, which is a target for activation of AMPK at the same time, is also an important target for neuropathic pain induced by chemotherapeutic drugs.[20],[33],[43] It is understood that MET can use these two different mechanisms to treatment in this type of neuropathic pain. Consequently, this study is the first report that emphasizes the important role of MET as an analgesic drug and considering available histopathological results by reversing damage in PAC-induced neuropathic pain.


 > Conclusion Top


According to our results MET has a neuron protective effect against paclitaxel induced neuropathic pain in rat model. Consequently, we suggest MET for patients who are suffering paclitaxel induced neuropathic pain.

Financial support and sponsorship

This work was supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK, Project Number: 113S083).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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