The potential effects of Caper (Capparis spinosa L.) in the treatment of diabetic neuropathy

Hamid Reza Esmaeilpour, Reza Boostani, Ali Shoeibi, Mojtaba Mousavi Bazzaz, Roshanak salari, Mahdi Yousefi*

The potential effects of Caper (L.) in the treatment of diabetic neuropathy

Hamid Reza Esmaeilpour1, Reza Boostani2, Ali Shoeibi3, Mojtaba Mousavi Bazzaz4, Roshanak salari5, Mahdi Yousefi1*

1Department of Persian Medicine, School of Persian and Complementary Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.2Department of Neurology and HTLV-1 Foundation, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.3Department of Neurology, Ghaem Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.4Department of Community Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.5Department of Pharmaceutical Sciences in Persian Medicine, School of Persian and Complementary Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Diabetic neuropathy (DN) is the most common form of neuropathy worldwide, with its prevalence rising alongside diabetes, and being characterized by sensory, motor or autonomic symptoms. DN is considered to be an incurable complication of diabetes, the management of which mainly consists of improving glycemic control, managing pain relief and ensuring continuous foot care. Although gabapentin, duloxetine and tricyclic antidepressants are commonly used to reduce patient symptoms, they do not affect the pathophysiology and progression of neuropathy. Furthermore, these drugs can have various side effects including insomnia, decreased appetite, arrhythmia, heart failure, and suicidal behavior.According totraditional Persian medicine, DN is recognized as a type of “or “(a sensory or motor disorder, respectively) that occurs due to the accumulation of sugars in the peripheral nerves.L., commonly known as the caper plant, has been recommended in authentic sources of traditional Persian medicine to treat such disorders.In this study, we reviewed the pharmacological properties ofusing the Web of Science, PubMed, Scopus and Google Scholar databases, and found thatL. could affect several pathways involved in DN pathogenesis, including aldose reductase activity, the secretion of inflammatory mediators (IL-17, TNF-α, IL-1β, IL-6), oxidative stress, hyperlipidemia, hyperglycemia and advanced glycation end product formation.Based on these findings, we hypothesize thatL., may prevent the progression and reduce the symptoms of diabetic neuropathy,and so canbe considered as a complementary treatment in this disorder. This hypothesis should be evaluated in well-designed in vitro and in vivo studies, and through clinical trials.

L.Diabetic neuropathy, Traditional Persian medicine, “

The authors hypothesize thatL., may prevent the progression of diabetic neuropathy, reduce its symptoms,and canbe considered as a complementary treatment for this disorder.

According to traditional Persian medicine, diabetic neuropathy is recognized as a type of “or “(a sensory or motor disorder, respectively) that occurs due to the accumulation of sugars in the peripheral nerves.L., commonly known as the caper plant,has been recommended as a treatment for such disorders by Avicenna (980 C.E.–1037 C.E.) and Razi (Rhazes) (864 C.E.–930 C.E.), two of the greatest scholars of traditional medicine.Different parts of the caper plant have been used in the treatment of rheumatism, gout, hypertension, diabetes, sciatica, as well as hepatic and splenic disorders.

Background

Neuropathy is a disorder of the sensory-motor or autonomic nerves and can result from various causes [1]. Currently, the most common cause of neuropathy worldwide, is diabetes [2, 3]. The prevalence of diabetes has increased in recent decades, mainly due to the changes in lifestyle [4]. Increased prevalence of diabetes will naturally be accompanied by an increase in diabetes related complications [5], with the most common complication of diabetes being neuropathy, generally affecting around 50% of diabetic patients [1, 6].Diabetic neuropathy (DN) progresses gradually over the years, and can have both physical and mental consequences, affecting patient quality of life [7]. A possible serious complication of DN is development of foot ulcers; the most common cause of non-traumatic amputation, and more often than other complications leads to the hospitalization of diabetic patients [8].

Several metabolic and immunologic pathways are involved in the pathogenesis of DN [9]. Oxidative stress, inflammation, glycation, ischemia and aldose reductase hyperactivity are mechanisms central to the cause of neural damage, with aldose reductase hyperactivity also leading to oxidative stress and the upregulation of some other pathogenic pathways[10, 11]. As such hyperglycemia plays a central role in the pathophysiology of this disorder [9]. Other conditions such as hypertension, hyperlipidemia and obesity may also increase the risk of developing DN. Currently DN is considered to be an incurable complication of diabetes, with its management mainly involving the improvement of glycemic control, managing pain relief and ensuring continuous foot care [3, 6]. Several drugs, including gabapentin, duloxetine and tricyclic antidepressants are currently used to reduce patient discomfort, however they do not affect the development of neuropathy and can also have various side effects, including decreased appetite, insomnia, suicidal behavior, dry mouth, arrhythmia and heart failure [12–14].

In traditional Persian medicine, DN is recognized as a type of “or “(a sensory or motor disorder, respectively) which occurs due to the excessive accumulation of sugars in the peripheral nerves[15].L., commonly known as the caper plant, has been recommended as a treatment for such disorders by Avicenna (980 C.E.–1037 C.E.) and Razi (Rhazes) (864 C.E.–930 C.E.), two of the greatest scholars of traditional medicine[16, 17].Different parts of the caper plant have been used in the treatment of rheumatism, gout, hypertension, diabetes, sciatica, as well as hepatic and splenic disorders [18, 19]. This plant is found in many different parts of the world, including the Mediterranean basin, North Africa, Europe, Middle East and Tropical Asia [19, 20]. The presence of several biochemical components, such as flavonoids, alkaloids, phenolic compounds, terpenoids, saponins, tocopherols, and carotenoids, have been reported in this plant [19, 21].

Given the lack of effective treatments for DN, the adverse effects of conventional drugs, as well as the recommendation ofL. for the treatment of sensory and motor disorders in traditional Persian medicine, we evaluated the pharmacological properties ofL. and potential effects of this plant in the treatment of DN.

Hypothesis

Based on the findings of this study,L.may be useful in the treatment DN, due to several pharmacological properties, including hypoglycemic, hypolipidemic, hypotensive, antioxidant, anti-inflammatory, analgesic, antiglycation, anti-obesity and neuroprotective effects, as well as the inhibition of α-amylase, α-glucosidase and aldose reductase activity, all of which could affect the underlying mechanisms of DN[22–32]. However, further investigation of these mechanisms is required. We therefore recommend further studies on the effects ofL.on DNand, if effective, the use of this plant or its derivatives in the treatment of this disorder.

Evidence supporting the hypothesis

According to the available scientific evidence, the beneficial effects ofL. on diabetic neuropathy can be explained as follows(Figure 1):

1.L. has exhibited antioxidant properties in different in vivo and in vitro investigations, by increasing the activity of antioxidant enzymes and removing free radicals [25, 33–39].

2. Several in vivo and in vitro studies have revealed the anti-inflammatory properties ofL. and the biochemical mechanisms through which the inhibition of different inflammatory signaling pathways can occur [26, 27, 40–44].

3.L.has been shown to decrease blood glucose levels in animal studiesand inhibit α-glucosidase (having an acarbose like effect on postprandial hyperglycemia) as well as pancreatic α-amylase activity in vitro [22, 23, 30, 31, 45]. In a placebo-controlled clinical trial of 54 patients with type II diabetes,L.significantly decreased blood glucose and HbA1c levels [46].

4. Lipid-lowering effects ofL.have been demonstrated in experimental investigations. It has been shown to significantly reduce the blood levels of low-density lipoprotein, total cholesterol and triglyceride, and increase high density lipoprotein in the healthy and diabetic animals [45, 47, 48]. It also causes a significant decrease in blood triglyceride and a non-significantdecrease in blood cholesterol and low-density lipoprotein in patients with type II diabetes [46].

5.L.has the beneficial effect of reducing blood pressure and preventing neural ischemia. It has exhibited vasodilatory and diuretic activity in normal rats, a function of lowering systolic blood pressure in spontaneous hypertensive rats [24], and anti-atherogenic properties in human and animal subjects [47, 49].

6.L.[50], and some of the flavonoids found in this plant (naringin, rutin, and quercetin), have been shown to have inhibitory effects on aldose reductase activity [32, 51], and thereby may prevent its pathogenic consequences and the activation of other deleterious pathways in diabetes.

7. Obesity significantly increases the risk of neuropathy in diabetic patients and is also associated with higher intensity neuropathic pain[52, 53].L.exhibits weight-loss effects in diabetic rats and high fat diet mice[23, 47], and therefore, may reduce the risk of obesity-induced neuropathy and patient discomfort.

8. Pain relief is one of the main therapeutic targets in DN, and the analgesic effect ofL.has been revealed in a rat model of osteoarthritis and rheumatoid arthritis [27]. This plant has also traditionally been usedto relieve various pains such as headache, toothache and rheumatism [54], which may be unrelated to its anti-inflammatory properties.

9. Several studies have reported the neuroprotective effects ofL.in Alzheimer’s disease, as well as in lipopolysaccharide-and D-galactose-induced cognitive impairment in animals [29, 44, 55].

10.L. inhibits the non-enzymatic glycation of biological molecules and preventsadvanced glycation end product formation during a hyperglycemic state in vitro, indicating that it may protect peripheral nerves in diabetes [28].

Prospective

Based on our hypothesis,L. and caper-derived medications may be helpful in the treatment of DN. Current evidence supports this suggestion, and can be summarized as follows:

1. DN results from a combination of multiple pathogenic conditions, including hyperglycemia, hyperlipidemia, inflammation, oxidative stress, advanced glycation end product formation, aldose reductase hyperactivity, obesity, hypertension, and nerve ischemia.

2. Most currently used drugs have mainly a palliative effect in DN and do not affect the pathologic processes or progression of the disease.

3. Due to its high prevalence, progressive nature, disabling consequences, high economic burden, and the insufficiency and side effects of conventional drugs, DN requires new, more effective and safe treatments.

4.L.and caper-derived medicinesmay be more effective than currently used drugs, as, in addition topalliative properties and fewer side effects [31], it may influence the underlying mechanisms of neuropathy.

5.L. has been recommended by Avicenna, Rhazes and some other traditional medical scientists to treat peripheral nerve disorders and had also been used by Romans in the treatment of paralysis [54]. However, in recent centuries, due to the discovery of various chemical drugs, the use of natural remedies has declined.

Despite this positive evidence, challenges remain to implementing such treatments for DN. The inhibition of pathogenic pathways in DN has been evaluated in several in vivo and in vitro studies. Although, these investigations have been associated with positive results, evidence for the effectiveness of such a treatment approach in human is still insufficient. In addition, some limitations of this hypothesis can be identified. For example, the mechanisms involved in DN, as well asL.’s effect on these, are still not well understood. There are also insufficient studies to confirm the effective components ofL. in DN. Furthermore, studying the precise effects ofL. on DN requires invasive methods such as nerve biopsy. Considering these issues,practical solutions are suggested as follows:

Figure 1 The beneficial effects ofL. on diabetic neuropathy.

1. The effects of caper on DN could be evaluated in an experimental study in rats. After induction of DN, rats could be randomly divided into intervention (L. extract) and control (no treatment) groups.

2. The effects ofL. on the sciatic nerve can be evaluated using behavioral tests (such as hot plate, tail flick, Von Frey, and formalin assays), as well as electrophysiological and histopathological studies at appropriate intervals and compared with the control group using statistical tests.

3. To investigate the effects ofL. on the progression of DN and patient symptoms, a randomized placebo-controlled clinical trial could be designed. The intervention group can receive caper extract and the control group a placebo. The severity of diabetic neuropathy can be assessed by standard questionnaires and electrophysiological tests before and after the study and compared using appropriate statistical tests.

Conclusion

The positive effects ofL. on the pathogenic pathways involved in DN, and therapeutic properties discussed in reliable sources of traditional medicine, indicate that this plant can be useful in the treatment of DN. However, further studies are warranted to properly establish the beneficial effects ofL. in practice.

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This study was supported by Mashhad University of Medical Sciences Research Council, Mashhad, Iran.

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DN, diabetic neuropathy.

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There are no conflicts of interest.

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Hamid Reza Esmaeilpour, Reza Boostani, Ali Shoeibi, et al. The potential effects of Caper (L.) in the treatment of diabetic neuropathy. Traditional Medicine Research 2020, 5 (6): 442–448.

: Nuo-Xi Pi.

: 11 December 2019,

5 January 2020,

:26 February 2020.

Mahdi Yousefi. Department of Persian Medicine, School of Persian and Complementary Medicine, Mashhad University of Medical Sciences,Vakilabad Blvd, Mashhad, Iran. E-mail: Yousefim@mums.ac.ir.

10.12032/TMR20200223167