Table of Contents    
ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 2  |  Page : 149-156  

The improvement of pain behavior and sciatic nerves morphology in mice model of painful diabetic neuropathy upon administration of ginger (Zingiber officinale Roscoe.) extract and its pungent compound, 6-shogaol


1 Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta; Department of Clinical and Community Pharmacy, Faculty of Pharmacy, Jember University, Jember, Indonesia
2 Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
3 Department of Histology and Cell Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia

Date of Web Publication18-Jul-2019

Correspondence Address:
Arief Nurrochmad
Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsbm.JNSBM_219_18

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   Abstract 


Background: 6-Shogaol is one of the bioactive compounds from ginger (Zingiber officinale Roscoe.) that had been widely used in many diseases. This research was aim to investigate the effect of ginger extract and its pungent compound, 6-shogaol on pain behavior and sciatic nerve morphology in mice model of painful diabetic neuropathy. Materials and Methods: Seventy-two male BALB/c mice were divided into nine groups. Diabetes was induced by single intraperitoneal injection of streptozotocin (STZ) 110 mg/kg body weight (BW). The mice were considered diabetic when the serum glucose level was at least 200 mg/dL. Thermal and mechanical hyperalgesia was measured using tail-flick latency and Randall–Selitto test once a week. Daily oral administration of 6-shogaol doses 5, 10, and 15 mg/kg BW, ginger extract doses 100, 200, and 400 mg/kg BW, or gabapentin dose 100 mg/kg BW was started at week 4. Diabetic mice without treatment and mice without STZ induction were used as controls. At week 7, the mice were euthanized, and paraffin sections of 1% osmium tetroxide-stained sciatic nerve samples were observed. Results: Ginger extract and 6-shogaol, but not gabapentin, produced dose-dependent lowering blood glucose effect. However, the mean of serum glucose level was not <200 mg/dL. After 4 weeks of hyperglycemia, the diabetic groups showed signs of hyperalgesia. The ginger extract, 6-shogaol, and gabapentin administration attenuated the hyperalgesic effect. The microstructure of sciatic nerves in diabetic mice that received ginger extract and 6-shogaol was less damaged compared to the diabetic control group. Conclusion: From this research, ginger extract and its pungent compound, 6-shogaol, showed anti-hyperalgesic and neuroprotective effects.

Keywords: 6-Shogaol, axon morphology, ginger extract, painful diabetic neuropathy, sciatic nerves, Zingiber officinale


How to cite this article:
Fajrin FA, Nurrochmad A, Nugroho AE, Susilowati R. The improvement of pain behavior and sciatic nerves morphology in mice model of painful diabetic neuropathy upon administration of ginger (Zingiber officinale Roscoe.) extract and its pungent compound, 6-shogaol. J Nat Sc Biol Med 2019;10:149-56

How to cite this URL:
Fajrin FA, Nurrochmad A, Nugroho AE, Susilowati R. The improvement of pain behavior and sciatic nerves morphology in mice model of painful diabetic neuropathy upon administration of ginger (Zingiber officinale Roscoe.) extract and its pungent compound, 6-shogaol. J Nat Sc Biol Med [serial online] 2019 [cited 2019 Aug 26];10:149-56. Available from: http://www.jnsbm.org/text.asp?2019/10/2/149/262955




   Introduction Top


Half of the diabetic patients suffer from diabetic neuropathy, and almost 50% of them report painful symptoms,[1],[2] such as hyperalgesia and allodynia.[1] Reduced glucose uptake induces cellular damage due to insufficient adenosine triphosphate production. Impairment of neurotrophic support, activation of protein kinase C, activation of poly (ADP-ribose) polymerase, and formation of advanced glycation end products in a diabetic individual [3],[4] modulate various biochemical pathways, which lead to structural and functional abnormality of the peripheral nerves including the sciatic nerves. Various cytokines and excitatory neurotransmitters also contribute to downregulation of the pain threshold.[1],[5] Therefore, the mechanism of painful diabetic neuropathy (PDN) development is very complex.

Due to its complex mechanism, the treatment of PDN is very challenging. Natural resources are an excellent material of choice because it allows mass production and increases the value to local products. One of the natural drug candidates for PDN is ginger. Recent studies reported that ginger showed some biological activities and efficacy to control hyperglycemia in vitro and in vivo and also showed efficacy in clinical trials for the diabetic patient.[6],[7],[8] The 6-shogaol, one of the pungent components in ginger, has been proven as an antioxidant and in an in vitro experiment demonstrated as a ligand to the transient receptor potential cation channel subfamily V member 1 (TRPV1), a polymodal receptor that is important in PDN pathophysiology.[9],[10] Activation of TRPV1 in diabetic mice induces action potential by increasing calcium influx and releasing neuropeptides including glutamate and causes pain.[11] However, prolonged TRPV1 activation, such as during capsaicin exposure, desensitized TRPV1 and reduced pain.[12],[13] There was a report that 6-shogaol activated TRPV1 channels by noncovalent bonding.[14] Based on an in silico moleculardocking study using AutoDock Vina software (http://vina.scripps.edu/), 6-shogaol had the highest affinity to TRPV1 compared to the other substances, i.e. 8-shogaol, 10-shogaol, 6-gingerol, 8-gingerol, and 10-gingerol.[15] Whether 6-shogaol attenuates hyperalgesia in PDN is yet to be elucidated.

In this study, the anti-hyperalgesic capacity of ginger extract and 6-shogaol is tested in streptozotocin (STZ)-induced diabetic mice that undergo PDN. Tail-flick latency and paw withdrawal threshold were used to measure the thermal and mechanical pain behavior, respectively. In addition, qualitative assessment of sciatic nerve's morphology will be presented.


   Materials and Methods Top


Materials

Rhizomes of ginger (Zingiber officinale var Roscoe.) were obtained from Klaten, Central Java, Indonesia, and identified in the Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia. Dried ginger (0.5 kg) was macerated three times (5 × 24 h) using ethanol 96% and evaporated to get the thick extract. The ethanolic extract from this process was obtained with the 5.6% yield.

The 6-shogaol was purchased from Chemfaces, Wuhan, China (CAS No. 555-66-8). Gabapentin was obtained from PT Indofarma, Indonesia. Dimethylsulfoxide, sodium carboxymethylcellulose, and phosphate-buffered saline (PBS) were purchased from Life Technologies Corporation (GIBCO), Singapore. Osmium tetroxide was purchased from Sigma-Aldrich Pte Ltd., Singapore. STZ was purchased from Nacalai Tesque Inc., Japan.

Animals

Seventy-two male BALB/c mice (30–40 g) were obtained from the Experimental Animal Unit, Animal Research and Development Centre, Universitas Gadjah Mada, Yogyakarta. The mice were housed and maintained under the standard conditions of 12-h light/dark cycle, 25°C ± 2°C, and 60%–70% humidity and had free access to food and water. All the animals were acclimatized for 1 week before experimentation. The experiment procedures were approved by the Institutional Animal Ethics Committee of the Integrated Research and Testing Laboratory, Universitas Gadjah Mada (number KE/FK/559/EC/2016).

Streptozotocin-induced painful diabetic neuropathy

Mice were fasted overnight for 14–16 h before the STZ induction. A single high dose of STZ of 110 mg/kg body weight (BW) (dissolved in freshly prepared cold citrate buffer 1.1%, pH 4.5) was administered intraperitoneally. One week after STZ induction, mice with serum glucose levels >200 mg/dl [16] were considered as diabetic and selected for the next experiments. Blood samples were obtained from the retro-orbital vein, and the serum glucose was measured using Glucose GOD FS kit (Diagnostic Systems GmbH, Holzheim, Germany) based on glucose oxidase-peroxidase method. Serum glucose was measured at baseline, 7 days after induction, and once a week at week 4, 5, 6, and 7. Mice BW were measured using an animal scale once a week. The mice were divided into nine groups, eight mice for each group, i.e., normal control (non-STZ induction), diabetic control (received vehicle); ginger extract (100, 200, and 400 mg/kg BW), 6-shogaol (5, 10, and 15 mg/kg BW), and gabapentin (100 mg/kg BW). Oral administration of the test substance was done once daily from week 4 after STZ induction until week 7. Diagram scheme of this research is illustrated in [Figure 1].
Figure 1: Diagram scheme of the research

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Pain behavioral testing

Pain behavioral testings were assessed before STZ injection (baseline) and every week until week 7. The tests were done 60 min after the administration of the test substance (ginger extract, 6-shogaol, and gabapentin). All tests were performed in three replications.

Tail-flick test

The thermal hyperalgesia was measured using tail-flick analgesiometer (Columbus Instrument, 1430, Ohio, USA). The tail of each mouse was exposed to a nichrome-radiant heat. The intensity of the heat was adjusted to give a basal latency range of 4–8 s in all mice. The mice that had response out of the range were excluded from the experiment. The tail-flick latency was defined as the time interval that was needed by mice to flick its tail after the exposure of the radiant heat. The maximum cutoff time was set to 15 s to prevent tissue damage.[17],[18] The percentage of maximum possible effect (MPE) was calculated according to the formula:[19] % MPE = (test latency – predrug latency)/(baseline cutoff latency – predrug latency) ×100.

Randall–Selitto test

The mechanical hyperalgesia was measured using Randall–Selitto paw pressure test analgesiometer (Ugo Basile SRL, Varese, Italy). An increasing mechanical force was directly applied to the dorsal surface of the hind paws of the mice through a conical probe until a withdrawal response, i.e. mouse paw withdrawal, vocalization or struggled, resulted. The point of application was marked with ink to maintain the location over repeated trials. The paw withdrawal threshold was recorded in gram, and the cutoff threshold was set at 250 g.[18],[20] The maximum possible effect was calculated according to the following formula:[19] % MPE = (test pressure threshold – pretest pressure threshold/(baseline cutoff pressure threshold – pretest pressure threshold) ×100.

Histological evaluation

On week 7, mice were euthanized, and the segment of the sciatic nerve exposed upon mid-thigh incision was removed and fixed in 10% paraformaldehyde in 0.1 M PBS (pH 7.4) overnight. The sciatic nerves were washed in PBS and then immersed in osmium tetroxide 1% for 3 days in 4°C. At day 4, the sciatic nerves were dehydrated gradually using ethanol, cleared in xylene, and embedded in paraffin. The thin (4 μm) sections were cut using a microtome before examination using a light microscope (Zeiss observer Z1, Massachusetts, USA).[21] The sciatic nerve morphology was compared between the groups.

Statistical analysis

The blood glucose level, BW, tail-flick latency, and paw withdrawal threshold were presented as mean ± standard error of the mean. Statistical differences between groups were analyzed using one-way ANOVA followed by post-hoc Tukey test if all values were eligible using normality and homogeneity tests (GraphPad InStat version 3.10; GraphPad Software Inc., La Jolla, CA 92037, USA). The P < 0.05 was considered statistically significant.


   Results Top


The effect of ginger extract and 6-shogaol on serum glucose levels and body weight

One week after STZ induction, the range of serum glucose level in diabetic groups was from 209.5 to 599.4 mg/dL with mean at 332.44 ± 39.50 mg/dL. The value was significantly higher compared to the normal control group (102.31 ± 5.74 mg/dL) (P < 0.001). The serum glucose level in diabetic groups increased until week 4 at a mean level 414.28 ± 52.72 mg/dl [Table 1] in the range of 205.38 mg/dL–678.4 mg/dL. After 3 weeks receiving ginger extract or 6-shogaol, at week 7, all of the ginger and shogaol groups showed significantly lower serum glucose level compared to the serum glucose level in the diabetic control group (514.22 ± 26.5 mg/dL; P < 0.001). It was noted that until week 7, the serum glucose level in all diabetic mice, except the group that received gabapentin, were still >200 mg/dL. The group that received gabapentin did not show a significant difference in the serum glucose level compared to the diabetic control group (P > 0.05). The groups received the highest dose of ginger extract 400 mg/kg BW and 6-shogaol 15 mg/kg BW had the lowest mean of serum glucose level at 221.95 ± 23.13 mg/dL and 208.25 ± 49.37 mg/dL [Table 1], respectively. Those two groups started to show significant lower serum glucose level at week 6, sooner than any groups that received 6-shogaol or ginger extract.
Table 1: Effect of ginger extract (Zingiber officinale Roscoe.) and 6-shogaol on serum blood glucose level in normal and diabetic mice

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The BW of normal control group increased along the experiment, but the BW of diabetic mice was decreased after STZ injection. At week 4, the diabetic groups had lower BW compared to the baseline and normal control groups (P < 0.001). At week 7, there was no significant difference in BW of the diabetic control group compared to the mice that received 6-shogaol (5, 10, and 15 mg/kg BW), ginger extract (100, 200, and 400 mg/kg BW), and gabapentin 100 mg/kg BW [Table 2].
Table 2: Effect of 6-shogaol and ginger extract (Zingiber officinale Roscoe.) on body weight change in normal and diabetic mice

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The effect of ginger extract and 6-shogaol on painful diabetic neuropathy

Before STZ injection, the mean tail-flick latency and paw withdrawal threshold were not significantly different than the normal control (P > 0.05). The mean value of tail-flick latency and paw withdrawal threshold was significantly decreased 1 week after STZ injection, indicating the hyperalgesia effect. The thermal and mechanical hyperalgesia persisted to decrease until week 4 (P < 0.001). Administration of ginger extract (100, 200, and 400 mg/kg BW) and 6-shogaol (5, 10, and 15 mg/kg BW) attenuated the decrease in tail-flick latency [Table 3] and paw withdrawal threshold [Table 4] in a dose-dependent manner (P < 0.001). The highest dose of ginger extract, 400 mg/kg BW and 6-shogaol, 15 mg/kg BW showed the best anti-hyperalgesic effect, better than gabapentin 100 mg/kg BW either in thermal or mechanical-induced hyperalgesia.
Table 3: The effect of ginger extract (Zingiber officinale Roscoe.) and 6-shogaol on thermal-induced hyperalgesia under painful diabetic neuropathy in mice

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Table 4: The effect of ethanolic extract (Zingiber officinale Roscoe.) and 6-shogaol on mechanical-induced hyperalgesia under painful diabetic neuropathy in mice

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Ginger extract and 6-shogaol produced similar maximum possible anti-thermal and mechanical hyperalgesic effect (MPE). However, the MPE of 6-shogaol was slightly higher than the ginger extract. The tail-flick latency showed that the administration of 6-shogaol dose 15 mg/kg BW had significantly higher MPE (111.49% ± 7.23%) than the diabetic group (12.93% ± 5.51%, P < 0.001) and was also significantly higher than gabapentin 100 mg/kg BW (73.29% ± 6.18%, P < 0.05), [Figure 2]. At week 7, the tail-flick latency in 6-shogaol dose 15 mg/kg BW group was not significantly different compared to the normal control group. However, the paw withdrawal threshold in the 6-shogaol dose 15 mg/kg BW group was still lower than the normal control group (P < 0.05).
Figure 2: Tail-flick latency of ginger extract (a) and 6-shogaol (b) versus control group. Paw withdrawal threshold of ginger extract (c) and 6-shogaol (d) versus control group. (e) Maximum possible effect of anti-hyperalgesia after administration of 6-shogaol and ginger extract (Zingiber officinale Roscoe.) under painful diabetic neuropathy in mice (week 7)

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The effect of ginger extract and 6-shogaol on axon morphology of sciatic nerves in painful diabetic neuropathy

Osmium tetroxide staining in sciatic nerve paraffin sections indicated that many myelinated axons were damaged at 7 weeks after STZ induction in diabetic mice compared to normal control. [Figure 3]a shows the morphology of the normal sciatic nerves, characterized with structured axons that are surrounded by the proportional thickness of myelin sheath to its diameter with many appearances of lipid droplets. The sciatic nerve of the diabetic control group [Figure 3]b showed thin myelin sheath and myelin debris. The group received ginger extract (400 mg/kg BW) [Figure 3]e, 6-shogaol (5 and 15 mg/kg BW) [Figure 3]c and [Figure 3]d and Gabapentin (100 mg/kg BW) [Figure 3]f showed less damage in the sciatic nerve's morphology. The highest dose of ginger extract and 6-shogaol demonstrated the sciatic nerve's morphology closer to the morphology of the normal control.
Figure 3: Histology of sciatic nerves with osmium tetroxide staining (×630). Figures show the sciatic nerves in the normal group (a) and diabetic group (b), 6-shogaol 5 mg/kg BW group (c), 6-shogaol 15 mg/kg BW group (d), ginger extract 400 mg/kg BW group (e) and gabapentin 100 mg/kg BW group (f). Arrows shows small axon with thin diameter of myelin and degeneration axon. Arrow heads shows axon with thick diameter of myelin. Asterix shapes showed lipid droplets in diabetic condition

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   Discussion Top


One week after STZ injection, the mice showed elevated blood glucose levels and started to show the sign of PDN, characterized by thermal and mechanical hyperalgesia. The sign of PDN persisted until week 4 after STZ injection. This result is similar to our previous report that 4 weeks was an optimum time to get an established PDN state.[22] On administration of the ginger extract or 6-shogaol for 3 weeks, the serum glucose level decreased in some groups, but the mean of the serum glucose level was still higher than the threshold for the diabetic condition used in this experiment, i.e., 200 mg/dL. Therefore, until the mice were euthanized at week 7, all of the STZ-induced mice were still considered as diabetic.

Although the serum glucose level did not reach normal range, 6-shogaol and ginger extract did reduce blood glucose in a dose-dependent manner in STZ-induced diabetic mice. However, after 3 weeks treatment, the serum glucose level in the mice receiving ginger or 6-shogaol did not reach the normal range, and the BW of the mice was not different from the BW of the diabetic control group, suggesting that the glucose-lowering effect of the ginger and 6-shogaol was very mild. Similar to previous research, longer ginger administration in rats [23] and higher dose of 6-shogaol 25–50 mg/kg BW for 6 weeks in diabetic mice failed to reduce blood glucose level equivalent to normal value.[24] 6-shogaol was reported to increase insulin secretion in diabetic rat but also not reach the normal value.[23] Another mechanism of the glucose-lowering effect of 6-shogaol was through increasing glucose utilization as reported in 3T3-L1 adipocytes and C2C12 myotubes in the absence of insulin.[25] The increased glucose utilization provides cellular energy to maintain cell integrity in a diabetic individual.[25]

The anti-hyperalgesic effect of 6-shogaol and ginger extract is probably due to 6-shogaol structural similarity to capsaicin, an analog TRPV1. 6-Shogaol has been reported as a potent and selective TRPV1 agonist which is equivalent to capsaicin.[10] Regulation of TRPV1 function by phosphorylation is altered in PDN and extending stimulation of TRPV1 in dorsal root ganglion reduced pain hypersensitivity due to desensitization of TRPV1.[12] Administration of 6-shogaol may stimulate and desensitize TRPV1, leading to the attenuation of pain detection to noxious stimuli. Reduced function of TRPV1 inhibits the activity of N-methyl D-aspartate receptor subtype 2B (NR2B), an important key molecule of chronic pain propagation.[26]

The maximum possible effect of 6-shogaol and ginger extract on thermal hyperalgesia was higher than their effect on mechanical hyperalgesia. In mechanical hyperalgesia, it was suggested that galanin receptors are involved in the effect of attenuation of PDN,[27] while the 6-shogaol target was TRPV1 that was more related to pain and thermal hyperalgesia. Nevertheless, there was an effect of ginger extract and shogaol on mechanical hyperalgesia. It might be caused by the mild glucose-lowering effect and increase utilization of glucose that prevented axonal damage and resulted in better peripheral nerve morphology. Whether there are other molecular targets of ginger extract and 6-shogaol related to its neuroprotection effect still needs to be elucidated.

The maximum possible effect of 6-shogaol was higher than ginger extract both on mechanical and thermal hyperalgesia. This effect may be due to higher amounts of 6-shogaol administered in 6-shogaol groups compared to the ginger extract group. One limitation of this study is the lack 6-shogaol concentration in the ginger extract. However, based on Ok and Jeong,[28] a total amount of 6-shogaol in ethanol extract of ginger was 3–5 mg/g. If this observation was integrated into our doses, there was 1.2–2 mg of 6-shogaol in the 100–400 mg ginger extract. This amount of 6-shogaol in the ginger extract was much lower than our 6-shogaol's single doses, i.e., 5–15 mg. To obtain the same doses of 6-shogaol, we needed 7–8-fold doses of ginger extract as much as 2.8–3.2 g. The dose volume will be >2.5 ml, the maximum volume of oral administration in mice. The maximum possible effect of 6-shogaol on mechanical and thermal hyperalgesia was also higher than gabapentin. Gabapentin did not affect glucose utilization; hence, it had slightly minimized nerve damage in the diabetic mice, and their effect was solely based on activating A21 site in calcium channel, which induced the release of Gamma-Aminobutyric Acid (GABA) and minimized pain.[29]


   Conclusion Top


From our study, we conclude that 6-shogaol and ginger extract alleviate thermal and mechanical pain behavior in mice model of PDN due to its effect in blood glucose stabilization and neuroprotection. There were many reports related to ginger supplementation in diabetic patients. Ginger extract has been tested in clinical trials for its glucose-lowering effect. Administration of dried ginger for a long period did not induce any adverse effect in diabetic patients. Therefore, clinical trials of 6-shogaol for diabetic neuropathy should be considered. Further study is also needed to elucidate the activity of 6-shogaol and ginger extract in TRPV1 and NR2B to explain their exact mechanism in PDN.

Acknowledgments

We would like to thank E.C. Hookom for his technical assistance in this manuscript.

Financial support and sponsorship

This work was financially supported by the Competency Grants Research (number: 2276/UN1-P. III/LT/DIT-LIT/2017) from the Ministry of Research, Technology and Higher Education, Republic of Indonesia.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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