A Systematic Review on Neuropathy

Injury to the nerves in animals are related to the pain models i.e., partial/total nerve transaction/ligation/chronic nerve constriction. Neuropathic pain can be a disabling side effect of cancer treatment. Chemotherapy induced peripheral neuropathy is toxic neuropathy that results from direct injury to peripheral nervous system. Experimental details of following behavior models observed in animals which are considered to indicate the pain are also included in the present review viz. a. autotomy (self-attack) b. hyperalgesia (withdrawal responses to moderate heat stimulus), c. allodynia (withdrawal in response to non-noxious tactile or cold stimuli). A range of drugs are available for symptomatic relief from neuropathic and inflammatory pain but these drugs have profuse side effects, most patients are still unsatisfied and many of them are refractory to existence medicines, this review also highlighted treatments available for neuropathic pain. Conservative drugs available for neuropathic pain are allied with life threatening side effects hence the role of drugs from natural source are the mainstay for its treatment, this review also hold the collection of studies reported on herbals and phytoconstituents in the neuropathic pain. Present review deals with basics of neuropathy, physiological and biological mechanism, animal models and treatment accessible for neuropathic pain. Aswar MK, Patil VR (2016) A Systematic Review on Neuropathy. Int J Drug Dev & Res 8: 029-034 Volume 8(2): 029-0234(2016)-030 Int J Drug Dev & Res ISSN: 0975-9344 pain may be vital to successful outcome. Several treatment options are offered by an interdisciplinary management team includes systemic medication, physical modalities (e.g., Physical rehabilitation), psychological modalities (e.g., behavior modification, relaxation training), invasive procedures (e.g., Triggerpoint injections, epidural steroids, sympathetic blocks), spinal cord stimulators, intrathecal morphine pump systems and various surgical techniques (e.g., dorsal root entry zone lesions, cordotomy and sympathectomy). But while offering these options caution is warranted as it may produce deaffrentation and exacerbate the underlying neuropathic mechanisms. So the mainstay for the management of NP is the tricyclic anti-depressants, anticonvulsants, local anaesthetics, corticosteroids, substance-p depletors, autonomic drugs and NMDA-antagonists. Tricyclic antidepressants (TCAs) TCA have been successfully used in the management of NP since last 25 years. Amitriptyline and Nortriptyline exerts their effect through the interactions with serotonin or norepinephrine neurotransmitter system [5]. But the use of anti-depressant is slowed down because of frequent side effects like hallucinations, dizziness, lightheadedness, dependence and abusability [6]. Anticonvulsants Phenytoin and carbamazepine are widely used as anticonvulsants. These drugs exert their membrane-stabilizing properties by blocking sodium channels specically and therefore reduce neuronal excitability in nociceptors. Carbamazepine is the drug of choice for the treatment of trigeminal neuralgia due to its potential sodium channel blocking action. Lamotrigine, new anticonvulsant has been tried as add-on treatment with carbamazepine in the treatment of trigeminal neuralgia [7]. Gabapentin, a novel anticonvulsant, the exact mechanism as either an anticonvulsant or an analgesic is unknown but proposed that it block the sub type of calcium channel on the neurons and thus reduces the pain. Venlafaxine hydrochloride, structurally novel antidepressant inhibits neuronal serotonin and norepinephrine re-uptake. Capsaicin Capsaicin derived from the chili pepper topically has been found to be beneficial in peripheral neuropathy. Depletion of substance P in the distal nerve endings is the proposed mechanism for its use in neuropathy [8]. Autonomic drugs Autonomic drugs which include the alpha-2 agonists (Clonidine) and alpha-1 antagonists (prazosin, terazosin). Both are proposed to produce analgesia by actions in the periphery, supraspinal CNS, and in the spinal cord. NMDA-Receptor antagonists Role of ionotropic glutamate receptors are well established in the hyperexcitability in peripheral neuropathy which eventually lead to allodynia and hyperalgesia. Drugs capable of modulating the NMDA receptor activity have been studied to alleviate neuropathic pain. Several NMDA receptor channel antagonists, including dextromethorphan, amantadine, memantine, and ketamine have been reported to relieve pain in various neuropathic pain states including phantom limb pain, central neuropathic pain, post herpetic neuralgia, and peripheral neuropathic pain [9]. Pharmacological inhibition of enzyme glutamate carboxypeptidase (hydrolyses N-acetylaspartylglutamate to produce glutamate) leading to decreased glutamate is associated with neuroprotective effects animal models of cisplatin, paclitaxel and bortezomib-induced peripheral neuropathy [10]. Preventive treatments The preventative treatment available for neuropathy must reduce the incidence or severity. These drugs not only reduce the neurotoxic effect of the chemotherapeutic agent, but also must maintain the anticancer effect. The agent includes drugs, vitamins, minerals, herbal remedies. Vitamin E: Vitamin E has been investigated for prevention of platinum drugs induced neurotoxicity. Cisplatin causes accumulation of platinum adducts in dorsal root of ganglia, and vitamin E may reduce that neurotoxicity via its antioxidant property. Some studies have shown that this antioxidant may protect nerves from the damage caused by cisplatin and paclitaxel and also protects against the microtubule dysfunction that caused by platinum drugs [11]. Amifostine: Amifostine is an organic thiophosphate and it has been studied primarily in cisplatin induced neuropathic pain that is thought to exert its neuroprotective function as a free radical scavenger. It is also effective as neuroprotectant in cisplatin and paclitaxel induced neuropathic pain [12]. Glutathione: Glutathione is primarily used in Cisplatin induced neuropathic pain (CIPN) [13]. Glutathione also affects the kidneys and may increase the elimination of cisplatin; this may contribute to its neuroprotective effect, but it may also diminish its antitumor activity. The proposed mechanism of glutathione interferes with the accumulation of p53 protein, which is activated by cisplatin [14]. Glutamine: Glutamine, endogenously present non-essential amino acid gets converted to essential amino acid in severe stress condition. It plays a vital role in the synthesis of glutathione in the body [15]. Glutamine has been studied for its protective role in CIPN. Vahdat et al. [16] proposed glutamine to protect against oxidative injury and regulate the nerve growth factor. Acetyl L-carnitine (ALC): Acetyl L-carnitine may modulate NGF expression; it may also promote regeneration following nerve injury [17]. ALC may block abnormal A-fiber and C-fiber nociceptor firing [18]. Herbal Treatment of Neuropathy In view of prominent adverse effects of modern medicine, drugs from natural sources offer safe therapeutic option in the treatment of neuropathy. Range of plants and phytoconstituents extensively studied for the management of neuropathy in rats (Table 1). Several active phytoconstituents like caffeic acid, phenethyl ester [19]; flavonoids like bioflavone, polyphenols [20] with reputable antioxidant and anti-inflammatory activity have been evaluated in the treatment of neuropathic pain. Isolated bioactive moieties from medicinal plant are documented as promising free radical scavengers playing crucial role in amelioration of neuropathy in animals. Animal Models in Neuropathic Pain Central pain models Weight-drop model (Allen technique): It is the most widely used model for the induction for spinal cord injury (SCI). SCI can be induced by dropping a fixed weight on the surgically exposed spinal dorsal surface at the lower thoracic-lumbar level [31-33]. SCI results in severe paraplegia and increased complete segmental necrosis [34,35]. Aswar MK, Patil VR (2016) A Systematic Review on Neuropathy. Int J Drug Dev & Res 8: 029-034 Volume 8(2): 029-0234(2016)-031 Int J Drug Dev & Res ISSN: 0975-9344 Excitotoxic spinal cord injury (ESCI): Intraspinal injection of quisqualic acid (QUIS), AMPA agonist can turn out long lasting spontaneous pain, mechanical allodynia and thermal hyperalgesia and neuronal loss in specific regions of the spinal gray matter in rat [36,37]. Peripheral nerve injury models Chronic constriction injury model (CCI or Bennett model): CCI is the well established and universally accepted animal model for the induction of neuropathy. In CCI, after thiopental sodium (35 mg/kg i.p.) anesthesia, skin of the lateral surface of the left thigh incised and a cut directly through the biceps femoris muscles to expose the sciatic nerve given. Ischemia can be induced by placing four ligatures (silk 4–0) around the nerve proximal part of the trifurcation at a distance of 1 mm between each ligature. Nociceptive thresholds be measured before and after performing surgery on different days, i.e., days 0, 1, 3, 6, 9, 1, 2, 15, 18, and 21 [1]. Partial sciatic nerve ligation model (PSL or Seltzer model): In PSL/PSNL, half of the left sciatic nerve ligated partially at the upper thigh level nylon suture. Three weeks after PSNL, allodynia and hyperalgesia could be evaluated after day 1. L5/L6 spinal nerve ligation model (SNL): Allodynia and hyperalgesia developed in SNL model in animals after unilateral ligation of L5 and L6 spinal nerves last for at least 4 months [38] and can be evaluated. Sciatic cryoneurolysis model (SCN): Freezing of the sciatic nerve as an alternative to complete transections or ligation, induces nerve injury in the SCN model [39,40] which leads to touch allodynia. Advantage of this method is that cryoneurolysis-induced nerve injury may be reversible, may be beneficial to study the effect of transient nerve injury and the healing process [41,42]. Peripheral neuropathy induced by diseases Diabetic neuropathic pain model (DNP): Many diabetic models are available, e.g., insulin deficient BB rats [43] and NOD mice [44,45], insulin resistant ob/ob and db/db mice [46,47], In addition, inflammatory the Mongolian gerbil [48,49], several chemicallyinduced models [50] can be used. The most commonly used model streptozocin-induced diabetic neuropathy model. Streptozocin kills insulin-secreting islet in rats, a single i.p. injection of streptozocin induces long lasting thermal and mechanical hyperalgesia, and cold and thermal allodynia [51,52].