Insight into the role of Inflammation in progression of Diabetes associated Neuropathy
Munish Kakar1, Pakhi Chakarborty1, Tapan Behl1*, Sukhbir Singh1, Neelam Sharma1,
Monika Sachdeva2
1Chitkara College of Pharmacy, Chitkara University, Punjab, India.
2Fatima College of Health Sciences, Alain, UAE.
*Corresponding Author E-mail: tapan.behl@chitkara.edu.in
ABSTRACT:
Diabetes is major fatal disease that gives the outbreak to the vast mortality rate in India. Most of the diabetic patients affected by foot ulcers and deposition of lesions in foot, arms, hands, and legs due to inflammation caused by means of various physical and chemical extremities contributing in the etiology of inflammatory diabetic neuropathy. In various neuropathic pains the most common is diabetic peripheral neuropathy (DPN) which affect leg region. It is characterized by the small and large nerve fibers autonomic alterations. The symptoms of DPN is basically occurs above the 50 years of age group. Inflammation, oxidative stress and mitochondrial dysfunction are the three main alterations involved in diabetic neuropathy. Inflammation persuades the stimulation of activator protein-1, nuclear factor kappa b (NF-Kb), and protein kinases stimulated by mitogen. Prolonged neuropathic damage in peripheral region will not be recovered, but there are many recent researches came out by which the progression of the lesion can be controlled by some effective measures. Many effective non-steroidal anti-inflammatory drugs have the potent actions on the peripheral pain in inflammatory diabetic neuropathy as well as multifocal sites in the polyneuropathy. Due to many complications occur in diabetes mellitus certain sites are prone to spread the inflammatory lesions, resulting in many difficult problems which can be treated as per the progression of the disease. Many patients were treated by the certain combinations of medication like prednisone and other non-steroidal anti-inflammatory diseases (NSAIDs), or can be diagnosed by the plasmapheresis and intravenous immune globulins.
KEYWORDS: Diabetic Neuropathy, Neuropathic Pain, Polyneuropathy, Plasmapheresis.
INTRODUCTION:
Type 2 is the most common form of diabetes mellitus which affect the most of the population in the country [3]. It is characterized by insulin resistance by which the insulin production slows down and the existing glucose level increases because there is no availability of insulin to regulate the respective glucose levels. It has been diagnosed most commonly in children, adults, and elder patients due to increase in the obesity and various physical inabilities. It is a bipolar disorder which affects both insulin secretion as well as insulin actions [4].
Figure 1: Types of diabetes mellitus.
COMPLICATIONS IN DIABETES MELLITUS:
The number of complications in different organs i.e. eye, blood vessels, kidney, and brain can occur due to this disorder due to consistent high level of blood glucose (Figure 2). Diabetic neuropathy is a very common complication occurs in mostly type 2 diabetic patient. When a response generated by a reaction produced by body’s immune system, then it is known as an inflammation [5-7]. The symbols of inflammation come out as redness, heat, swelling, pain, and functional loss. Diabetic neuropathy is disease caused by nerve damage [8]. It is derived mainly from the disease called diabetes mellitus. It is a secondary complication in diabetic patients [9]. Diabetic neuropathy is a result of sensational defects occurs in feet and legs which are most common in every 70-80% diabetic patients [10]. Many functions get altered due to diabetic neuropathy such as GIT problems, lack of sensation caused by tingling of neurons in the wrist (carpel tunnel syndrome) [11]. The most common type of neuropathy is distal and peripheral neuropathy on the basis of impaired fibers of myelinated and unmyelinated. Diabetic polyneuropathy is the result of destruction of many small and unmyelinated fibers (C fiber) [11]. Due to complexity in cellular and lipid metabolisms it is very challenging task to search for the treatment for diabetic neuropathy [12]. The impairment in various glucose and lipids cellular metabolism influences following biochemical pathways which includes elevated oxidative/nitrostative stress, polyol or protein kinase C pathway stimulation, stimulation in polyADP ribosylation and initiative stimulation in genes which causes the damaging of nerve, activation of cyclooxygenase-2 (inducible enzyme) which releases the various inflammatory mediators like prostaglandins (PG) and thromboxanes (TXA) responsible for inflammation. The various pumps are also altered due to nerve damage like Na+/K+- ATPase pump, peptide signaling function (especially peptide C), endoplasmic reticulum load [13]. The diabetes 2 patients mostly suffered from low-grade inflammation which results in various anabolic and catabolic abnormalities and derangement occurs in blood circulation which release inflammatory biomarkers like cytokines, adhesion molecule, and dysfunction in endothelial membrane. All biomarkers affect the microvasculature lead to diabetic neuropathy [14].
Figure 2. Complications in different organs due to diabetes mellitus.
DIABETIC NEUROPATHY:
Symptoms:
Symptoms of diabetic neuropathy appear on the basis of severity of the disease and the area where the nerve damage occurs. As the damage is increased the symptoms are also increases gradually and pain becomes severe [15]. General symptoms include pain, lack of sensation (numbness), and tingling (weakness). The severity of pain indicates the control measurement of the disease [16]. The large number of population of diabetes is affected by peripheral neuropathy which affects organs such as legs, arms, feet and hands. The nerves of leg region are long that’s why the most common affect regions are the leg [2,11,15]. The symptoms include pain, swelling, electric shock sensations, and lack of sensitivity towards pain and highest degree of sensitivity to even in the lightest touch. Hypoglycemic unawareness in autonomic neuropathic patients is extremely dangerous due to which low blood sugar level cannot be detected in diabetic subjects [11,17-19]. Symptoms appear in different systems of biological entity such as frequent urination at night (urinary system), abnormal perspiration specially in legs and feet (sweat glands), erectile dysfunction and dryness in vagina (reproductive system) and bloating, nausea and vomiting (digestive system). High resolution ultrasound (HRUS) is used to examine the inflammation in multi peripheral nerve endings in a short duration window [20]. It also predicts the unmyelinated fibers with enlarged ends which confirm the site of inflammation. All the examination shows enlargement depending upon subject nerve condition due to various external and internal factors [2].
Epidemiology:
It is one of the most common diseases caused by the nerve damage due to increase in glucose level which affect the central and peripheral parts of the body [21]. According to world health organization (WHO) data analyzed in 2014, it has been found that diabetes affects the population by 422 million adults and it is raised up to 510 million populations in the year 2017. Many researchers illustrated that 50% of population has been affected by the diabetic foot ulcer [22].
Role of inflammatory mediators:
The neuropathic pain is a result of many of various inflammatory mediators such as cytokines, and nuclear factor kappa B (NF-κB). Various mechanisms were proposed by researchers such as enhanced production of oxygen species, elevated glycolysis, irregulated outflow in neurovascular cells, and decreased effect in nerve cells (Figure 3) [23]. In many studies, it is known as NF-κB pathway in which it is stimulated by a number of stimuli characterized to produce different types of inflammatory and immune mediators [24]. Types of different mediators involved are toll like receptors (TLR) consumed by the innate immune system [25]. NF-κB level gets increased by the activation in TLR specially TLR2 and TLR4. Two main forms of TLR4 gene are Thr399Ile and Asp299Gly which impaired the structure of extracellular domain by polymorphism which alters the binding ability of ligand molecule [22,25]. Cytokine includes interleukins, chemokines, tumor necrosis factor (TNF-α), and cyclooxygenase (COX) [26]. Interleukins are the mediators having the ability to communicate with leukocyte. According to the current data, isoforms IL-1, IL-6 and IL-8 have pro-inflammatory while IL-4 and IL-10 have anti-inflammatory actions [27]. Chemokines also called as chemical cytokines fundamental part of immune system which is involved in nociceptive behavior which influenced by the harmful stimuli [22,28]. The mechanism of cytokines was analyzed by the regulated on activation normally T-cell expressed and secreted (RANTES). TNF-α is a pro-inflammatory mediator induces nociceptive behavior [29]. COX is rate dependent enzyme for PG production and blocking the receptors for acting NSAIDs. Two isoforms of COX are COX-1 which is constitutive while COX-2 which induces the inflammation. COX-2 makes the cells enough for analyzing the state of inflammation in the tissues [30].
Figure 3. Mechanism of nerve damage or dysfunction induced by hypoglycemia. MAPK: mitogen activated protein kinase, AP: activator protein, nf-κb: nuclear factor kappa b, il- interleukins.
Mechanism of inflammation in diabetic neuropathy:
The major causes of all the complications are hyperglycemia, where insulin resistance and dyslipidemia have also impact on this disease. In polyol pathway, excess glucose is metabolized by polyol pathway in which it is reduced to sorbitol by increasing the concentration of sorbitol and decreasing the intake of inositol [31]. This alters the function of Na+/K+ ATPase pump and the conduction velocity of nerve cells slows down which lead to the damage of peripheral nerve results in peripheral neuropathy. Others pathways are also involved in it like advanced glycation end (AGEs) pathway in which glucose is binds with AGE [32].
Inflammation and growth factors:
The chronic symptoms are responsible for diabetic neuropathy and the neuropathic pain occurred due to pro-inflammatory mediators such as TNF-α, IL-1, IL-6, IL-8, MCP-1 and C-RP amplify the progression and increased level of the disease (Figure 4). According to many experiments performed by researchers it has been proved that TNF-α plays a major role in DN [33-35]. The increased level of TNF-α has been found in the bloods of diabetes 1 and 2 subjects. While in mice there is no progression of nerve damage occur due to alteration in TNF-αgene knockout [36-38]. The activation of immune cells produces the pro-inflammatory cells while others are secreted by macrophages and adipose cells. The enhanced expression of adhesion molecule and endothelium activation is stimulated by the release of chemokines from injured cell or tissues. The adhesion molecules such as intracellular adhesive molecule-1 (CAM-1), vascular adhesive molecule-1 (VCAM-1) and E-selectin associate diabetic neuropathy [34]. The growth and survival of neurons are regulated by the neurotrophic factors give rise to the development of nervous system. The nutrition to nerve cells are given by nerve growth factors (NGF), brain derived neurotrophic factor (BDNF), neurotrophins-3 and 5 (NT-3 and NT-5) [23,37]. The main roles of the nutrition factors are to promote the growth and the viability of the nerve cells and to control the destruction of myelin sheath [38]. Due to release in inflammatory mediators DN tissues are deprived of NGF and NT-3 which lead to the nerve damage which also decreases the transport of NGF and NNT-to the peripheral nerves in the experiment of mice it was observed by many scientists that the enhanced spreading of myelin fibers in foot skin of DN are due to intrathecal entry of NGF and NT-3. Schwann cells are also responsible for the release of many growth factors [39]. So it has also a great impact on DN. Glia derived neurotrophic (neureglin-1) factors binds with the B2 Erb receptors present in schwann cells which promote the viability and the production of myelin sheath [40]. From a study it has been proved that the degeneration after axonal damage was induced by the elevated level of neureglin forms [41,42]. From many research studies it has been found that the innate immune system is producing low grade inflammation response towards these complications. The neuropathic complication occurs in diabetes type II subjects. The increase in the pro- and anti-cytokines concentration and other inflammatory mediators which stimulate immune system is responsible for the low grade response [43,44]. Other complication due to neurodegeneration in type II diabetes patients can cause atherosclerosis or tumor growth and can also alters the physiological functions. Many experimental studies showed that the major inflammation occurs in DN is due to stimulation of IL-6 and IL-10 with abnormal nerve fibers whereas IL-10 is an anti-inflammatory cytokine, therefore the reimburse mechanism is produced for increased level in IL-1 [45].
Figure 4: Inflammation and growth factors in hyperglycemias induced diabetic neuropathy.
Due to activation of all the above pathways
the inflammatory mediators induces the termination of enzyme activity. The activation
of all the biochemical pathways like oxidative/nitrative stress pathways are under
the influence of complex pathogenesis of diabetic neuropathy and the imbalances
occur due to liberation of inflammatory mediators, biomarkers, cytokines-8, the
impairment of polyol and myo inositol pathway, reduction in Na+/ATPase activity
during nerve impulse generation, defect in transport across the axonal membrane,
due to insufficient transport of oxygen supply which cause transient ischemic attack,
all influenced by the complex pathophysiology of DNA. Lack of sensitivity causes many stumbling
blocks in the biological system:
· Consistent pressure build up for prolonged hours which lead to local ischemia.
· Immediate injuries which results from high pressure build up for smaller duration
· Inflammatory autolysis of tissues results from the successive moderate pressure.
Role of immune cells in inflammation:
Macrophages are involved in the progression of inflammation. There are two main types of macrophages are there which are involved and active M1 (pro-inflammatory active), and M2 (anti-inflammatory and alternative active) [4]. In the middle stage of DN many infiltrated macrophages are follow the M1 type macrophages and involved in the progression of the disease [46]. The locations of these macrophages are not précised. The production of NF-κB is induced by the signaling of TNF-α through a JAK/STAT pathway [11,17]. TLR signaling along with M1 macrophages produces the classical pathway with adapter protein Myd88. Collectively, M1 type is the main causation agent for inflammation as it increases the progression of the inflammation but on the other side M2 types involves in the healing process [35,47,48]. Helper T cells are also play an important role in inflammation. It does not have potent efficacy towards inflammation than other immune cells [35]. One of the helper T cell is CD4+ T cells which once activated produces the different signs of inflammation and trigger the release of chemokine. Many of the other helper T cells like Th1, Th2, Th17, Th9 and Th22 which results into the splitting of helper T cells into T regulatory phenotypes. These cells are having the ability to release cytokines. After activation of many of the mediators, T helper cells pass through many functional stages undergoes apoptosis [29,32]. All the stimulation or release of mediators is regulating by the immune cells response but the origin etiology of this neurodegeneration is unpredictable [42,49,50].
Inflammation and diabetic neuropathy:
Several pre-clinical and clinical [51] trials determine the role of inflammation mainly cytokine in the pathogenies of diabetes neuropathy. Though inflammation is a multifaceted process, stimulation of NF-κB plays a major role. NF-κB is a redox-sensitive transcriptional factor triggered by oxidative stress, and inflammatory mediators. Numerous indications attained in experimental models protrude that regulation of the NF-κB axis elicit inflammatory and immune responses which induces cellular injury. In a streptozotocin (STZ)-induced diabetes model, ischemia reperfusion damage persuades NF-κB overproduction in the diabetic sciatic endothelial cell with macrophages infiltration proposing that the inflammatory response in diabetic nerves was induced by NF-κB activation [52]. The NF-κB encourages the manifestation of several inflammatory genes such as cyclooxygenase-2 (COX-2), NO-synthase, lipoxygenase, and endothelin-1 was studied in animal models of DN [53]. The NF-κB-derived cytokine TNF-α stimulate cyclooxygenase-2 (COX-2) overproduction and mitogen activated protein kinase (MAPK) regulation involved in the diabetes-induced pro-inflammatory and neuropathic alteration. In two animal models of T1DM neuropathy, one group found elevated levels of TNF-α in the sciatic nerve of diabetic rats and mice which were accompanied with both large and small nerve fiber dysfunction in the diabetic models. These changes were inhibited by either COX-2 gene inactivation or treatment with a COX-2-selective inhibitor [54]. In another model of diabetes, constraining of 12/15 lipoxygenase increases motor and sensory nerve conduction velocities (NCV) [53]. One group has also reported up-regulation of multiple inflammatory cytokines, such as COX2, iNOS, and TNF-α, in sensory neurons of db/db mice when the animals are suffering from pain [55]. Inhibiting the increase in these inflammatory mediators prevent pain, signifying that in an experimental model of T2DM DN, inflammation in sensory neurons can result in pain. IL-6 is secreted with TNF-α and is considered as a pro-inflammatory cytokine. Although, it has been revealed that treatment of diabetic rats with pharmacological medication of IL-6 improved motor and sensory NCV [53,56-61].
Treatment of inflammatory diabetic neuropathy:
Many researchers said that the treatment of diabetic neuropathy is predicted by some animal experiments [47]. There are many failure therapies which were translated by FDA approved therapy and many unsuccessful outcomes are induced by some of the unpredictable factors [33]. These factors lead to study of the clinical and the preclinical studies in the diagnosis and treatment of pre and post progression of the disease [32]. The treatment inflammatory mediator is conclude by the administration of the inflammatory mediator blockers or inflammation inhibitors which mainly target the TNF-α, IL-1, IL-6, IL-8 and IL-22 [4,38,39]. The treatment with the NSAIDS is the prolong treatment for the action [44]. Flurbiprofen inhibits the COX-1 enzyme by inducing STZ (streptozocin) which is followed by the MNCV (motor nerve conduction velocity) which decreases the area of myelinated fibers, nerve density; enhance the axonal damage [49]. Proxicam inhibits the mimic action of STZ. The main target for the therapeutic treatment of the DN is the site of release of inflammatory mediators [48]. Some complication lead to implicit the administration of placebo with many of the subjects such as ibuprofen and sulindac [38,42]. Some COX-2 inhibitors would recommend preventing the various GIT side effects. But in some cases it altered by the antidepressants (venlafaxine, bupropion, and duloxetine), antiepileptic or anticonvulsant drugs (valproate, pregabalin, and gabapentin) which are neither selective nor problematic as NSAIDs [45]. The main mechanism of the anticonvulsant drugs are to block the Na+ (felbamate, lemotrigine) and Ca2+ channels as they stimulate the release of chemokines [40]. Other treatments include surgical removal of damaged nerve, implantation by inserting a device, and stimulation by electrical signals to the nerve [46,50,55,58].
CONCLUSION:
There is still not any exact treatment found for the diabetic neuropathy. Due to lack of clear concept about the activation of following factors such as nuclear factor kappa b, activator proteins which alter the glycemic target in body tissues. For the permanent cure of this disease the subject may take a precautive step by controlling the diet and exercise. Many researchers found it helpful to treat the neuropathic damage by knowing the past medical history and the present damaged region. Since the control on glucose is achieved by or to modify the overproduction of reactive oxygen species (ROS). Many clinical trials are being performed by the research scholars to predict the treatment and pre-diagnosis of the neuropathic damage. Various other methods such as nerve biopsy which examine the inflammatory infiltration in perivascular region and immunotherapy are also useful for predicting the cause of inflammation. Over the counter products like acetaminophen, stimulate the inhibition of blockade of inflammatory mediators release and also reduces the pain. Some hypothesis suggests that the inflammation occurs at early stage of diabetes with insulin resistance. The inflammation factors create many complications which can heal by the inflammatory healing procedures. Collectively, the data from experimental diabetes and from both serum and neural gene expression studies in patients with DN strongly support a role for inflammation in the onset and progression of DN. We contend that targeting inflammation is a mechanism-based strategy critically needed in the field of DN and it may be the missing link in finding a new viable therapy for DN. All of these complications cause many endothelial dysfunction and metabolic disturbances which results in the deposition of non-metabolic fats increases the level of glucose. NSAIDs are given to inhibit the release of inflammatory mediators which stimulate the activations of inflammatory factors which can be given by over-the-counter or in prescription form. Overall this paper concludes all the etiological aspects with healing methods of inflammatory diabetic neuropathy which is the main complication occurred in type II diabetes mellitus.
ACKNOWLEDGEMENT:
The authors are thankful to Chitkara College of Pharmacy, Chitkara University, Punjab, India for providing facilities for compilation of this review.
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Received on 09.01.2020 Modified on 13.02.2020
Accepted on 17.03.2020 © RJPT All right reserved
Research J. Pharm. and Tech. 2020; 13(11):5477-5483.
DOI: 10.5958/0974-360X.2020.00956.7