Alcoholic Neuropathy: Involvement of Multifaceted Signalling Mechanisms.

BACKGROUND: Alcoholic neuropathy is a chronic disorder caused by the excessive consumption of alcohol. Damage to the nerves results in unusual sensations in the limbs, decreased mobility and loss of some body functions. OBJECTIVE: Alcohol is considered a major cause for exclusively creating the debilitating condition of the neuropathic state. This review critically examines the key mediators involved in the pathogenesis of alcoholic neuropathy and the targets, which, upon selective inhibition, alleviate the progression of alcoholic neuropathy. METHODS: A thorough study of research and review articles available on the internet from PubMed, MEDLINE, and concerned sites was performed on alcoholic neuropathy. RESULT: Impairment in axonal transportation is quite common with the progression of alcoholic neuropathy. Nutritional deficiencies lead to axonal neuropathies that escalate a variety of complications that further worsen the state. PKC and PKA play a significant role in the pathogenesis of alcoholic neuropathy. PKC plays a marked role in modulating NMDA receptor currents, manifesting excitations in neurons. MMPs are involved in the number of pathologies that destroy the CNS and reduction in the level of endogenous antioxidants like α-tocopherol, vitamin E with ethanol, promotes oxidative stress by generating free radicals and lipid peroxidation. CONCLUSION: Oxidative stress is implicated in the activation of MMPs, causing disruption in the blood-brain barrier, the latter are involved in the trafficking and passage of molecules in and out of the cell. Chronic alcohol consumption leads to the downregulation of CNS receptors, consequently precipitating the condition of alcoholic neuropathy.

Chronic Neurologic Effects of Alcohol.

Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.

Independent contributions of alcohol and stress axis hormones to painful peripheral neuropathy.

Painful small-fiber peripheral neuropathy is a debilitating complication of chronic alcohol abuse. Evidence from previous studies suggests that neuroendocrine mechanisms, in combination with other, as yet unidentified actions of alcohol, are required to produce this neuropathic pain syndrome. In addition to neurotoxic effects of alcohol, in the setting of alcohol abuse neuroendocrine stress axes release glucocorticoids and catecholamines. Since receptors for these stress hormones are located on nociceptors, at which they can act to cause neuronal dysfunction, we tested the hypothesis that alcohol and stress hormones act on the nociceptor, independently, to produce neuropathic pain. We used a rat model, which allows the distinction of the effects of alcohol from those produced by neuroendocrine stress axis mediators. We now demonstrate that topical application of alcohol and exposure to unpredictable sound stress, each alone, has no effect on the nociceptive threshold. However, when animals that had previous exposure to alcohol were subsequently exposed to stress, they rapidly developed mechanical hyperalgesia. Conversely, sound stress followed by topical alcohol exposure also produced mechanical hyperalgesia. The contribution of stress hormones was prevented by spinal intrathecal administration of oligodeoxynucleotides antisense to ß(2)-adrenergic or glucocorticoid receptor mRNA, which attenuates receptor level in nociceptors, as well as by adrenal medullectomy. These experiments establish an independent role of alcohol and stress hormones on the primary afferent nociceptor in the induction of painful peripheral neuropathy.

Evaluation of ameliorative effect of quercetin in experimental model of alcoholic neuropathy in rats.

OBJECTIVE: The objective of the present investigation was to study the neuroprotective effect of the quercetin in alcohol induced neuropathy in rats. MATERIALS AND METHODS: Male Wistar rats were administered alcohol (10 gm/kg, 35% v/v, p.o. b.i.d.) for 10 weeks. Alpha tocopherol (vitamin E) was used as a standard drug. Vitamin E (100 mg/kg) and quercetin (10, 20 and 40 mg/kg) were co-administered 1 h after ethanol administration for 10 weeks. Behavioral assessment parameters, such as motor incoordination, tactile allodynia, mechanical and thermal hyperalgesia were recorded in all groups of animals. Meanwhile, motor nerve conduction velocity was also recorded. Biochemical parameters, such as nitric oxide (NO), Na(+)-K(+)-ATPase, malondialdehyde (MDA) and myeloperoxidase (MPO) were estimated in sciatic nerve. Apoptosis index was determined with help of DNA fragmentation in sciatic nerve. RESULTS AND DISCUSSION: Chronic ethanol administration for 10 weeks resulted in significant (P < 0.001) development of neuropathic pain. Chronic treatment with quercetin (20 and 40 mg/kg) for 10 weeks significantly (P < 0.001) attenuated allodynia, hyperalgesia as well as motor coordination and impaired nerve conduction velocity along with decreased level of membrane-bound Na(+)-K(+)-ATPase. It also significantly (P < 0.001) decreased elevated levels of MDA, MPO as well as pro-inflammatory mediators, such as NO. It also decreased the extent of DNA fragmentation. This alteration was more significant in vitamin E treated rats (100 mg/kg). Quercetin is a proven antioxidant that might have decreased the oxidative stress produced by chronic alcoholism. CONCLUSION: The present investigation elucidates neuroprotective effect of quercetin in alcohol induced neuropathy through modulation of membrane-bound inorganic phosphate enzyme and inhibition of release of oxido-inflammatory mediators, such as MDA, MPO and NO.

Therapeutic role of curcumin in prevention of biochemical and behavioral aberration induced by alcoholic neuropathy in laboratory animals.

Painful peripheral neuropathy induced by chronic ethanol consumption is a major medico-socioeconomical problem. The objective of present investigation was to study the effect of curcumin (20, 40 and 80mg/kg; p.o.) in alcohol-induced neuropathy in rats. Ethanol (35% v/v, 10g/kg; p.o.) was administered for 10 weeks which showed a significant decrease in thermal hyperalgesia, mechanical hyperalgesia, mechanical allodynia and nerve conduction velocity. It caused enhanced malondialdehyde, oxidative-nitrosative stress, total calcium levels, inflammatory mediators (TNF-α and IL-1ß levels) along with DNA damage. Co-administration of curcumin and α-tocopherol for 10 weeks significantly and dose-dependently improved nerve functions, biochemical as well as molecular parameters and DNA damage in sciatic nerve of ethanol treated rats. Hence, it was concluded that curcumin is of potent therapeutic value in the amelioration of alcoholic neuropathy in rats and acts by inhibition of pro-inflammatory mediators like TNF-α and IL-1ß.

Alcohol-related peripheral neuropathy: nutritional, toxic, or both?

Alcohol-related peripheral neuropathy (ALN) is a potentially debilitating complication of alcoholism that results in sensory, motor, and autonomic dysfunction. Unfortunately, ALN is rarely discussed as a specific disease entity in textbooks because it is widely assumed to primarily reflect consequences of nutritional deficiency. This hypothesis is largely based on observations first made over eight decades ago when it was demonstrated that thiamine deficiency (beriberi) neuropathy was clinically similar to ALN. In recent studies, failure of thiamine treatment to reverse ALN, together with new information demonstrating clinical and electrophysiological distinctions between ALN and nutritional deficiency neuropathies, suggests that alcohol itself may significantly predispose and enhance development of neuropathy in the appropriate clinical setting. We reviewed the evidence on both sides and conclude that ALN should be regarded as a toxic rather than nutritional neuropathy.

Amelioration of functional, biochemical and molecular deficits by epigallocatechin gallate in experimental model of alcoholic neuropathy.

Long term alcohol consumption leads to decreased nociceptive threshold characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism involved in this pain includes increased oxidative-nitrosative stress, release of pro-inflammatory cytokines and neuronal apoptosis. The present study was designed to explore the protective effect of epigallocatechin-3-gallate against alcoholic neuropathic pain in rats. Rats fed with alcohol (35%) for 10 weeks showed markedly decreased tail flick latency in tail-immersion test (thermal hyperalgesia), vocalization threshold in Randall-Sellito test (mechanical hyperalgesia) and paw-withdrawal threshold in von-Frey hair test (mechanical allodynia) along with enhanced oxidative-nitrosative stress and inflammatory mediators (TNF-α, IL-1ß and TGF-ß1 levels). Co-administration of epigallocatechin-3-gallate (25-100 mg/kg) significantly and dose-dependently prevented functional, biochemical and molecular changes associated with alcoholic neuropathy. In conclusion, the current findings suggest the neuroprotective potential of epigallocatechin-3-gallate in attenuating the functional, biochemical and molecular alterations associated with alcoholic neuropathy through modulation of oxido-inflammatory cascade.

Alcohol consumption enhances antiretroviral painful peripheral neuropathy by mitochondrial mechanisms.

A major dose-limiting side effect of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) chemotherapies, such as the nucleoside reverse transcriptase inhibitors (NRTIs), is a small-fiber painful peripheral neuropathy, mediated by its mitochondrial toxicity. Co-morbid conditions may also contribute to this dose-limiting effect of HIV/AIDS treatment. Alcohol abuse, which alone also produces painful neuropathy, is one of the most important co-morbid risk factors for peripheral neuropathy in patients with HIV/AIDS. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV/AIDS patients, the mechanisms by which alcohol abuse exacerbates highly active antiretroviral therapy (HAART)-induced neuropathic pain has not been demonstrated. In this study, performed in rats, we investigated the cellular mechanism by which consumed alcohol impacts antiretroviral-induced neuropathic pain. NRTI 2',3'-dideoxycytidine (ddC; 50 mg/kg) neuropathy was mitochondrial-dependent and PKCε-independent, and alcohol-induced painful neuropathy was PKCε-dependent and mitochondrial-independent. At low doses, ddC (5 mg/kg) and alcohol (6.5% ethanol diet for 1 week), which alone do not affect nociception, together produce profound mechanical hyperalgesia. This hyperalgesia is mitochondrial-dependent but PKCε-independent. These experiments, which provide the first model for studying the impact of co-morbidity in painful neuropathy, support the clinical impression that alcohol consumption enhances HIV/AIDS therapy neuropathy, and provide evidence for a role of mitochondrial mechanisms underlying this interaction.

Tocotrienol ameliorates behavioral and biochemical alterations in the rat model of alcoholic neuropathy.

Chronic alcohol consumption produces a painful peripheral neuropathy for which there is no reliable successful therapy, which is mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy is characterized by spontaneous burning pain, hyperalgesia (an exaggerated pain in response to painful stimuli) and allodynia (a pain evoked by normally innocuous stimuli). Chronic alcohol intake is known to decrease the nociceptive threshold with increased oxidative-nitrosative stress and release of proinflammatory cytokines coupled with activation of protein kinase C. The aim of the present study is to investigate the effect of both isoforms of vitamin E, alpha-tocopherol (100mg/kg; oral gavage) and tocotrienol (50, 100 and 200mg/kg; oral gavage) against alcohol-induced neuropathic pain in rats. Male Wistar rats, were administered 35% v/v ethanol (10 g/kg; oral gavage) for 10 weeks, and were treated with alpha-tocopherol and tocotrienol for the same duration. Ethanol-treated animals showed a significant decrease in nociceptive threshold as evident from decreased tail flick latency (thermal hyperalgesia) and decreased paw-withdrawal threshold in Randall-Sellito test (mechanical hyperalgesia) and von-Frey hair test (mechanical allodynia) along with the reduction in nerve glutathione and superoxide dismutase levels. TNF-alpha and IL-1beta levels were also significantly increased in both serum and sciatic nerve of ethanol-treated rats. Treatment with alpha-tocopherol and tocotrienol for 10 weeks significantly improved all the above-stated functional and biochemical deficits in a dose-dependent manner with more potent effects observed with tocotrienol. The study demonstrates the effectiveness of tocotrienol in attenuation of alcoholic neuropathy.

Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy.

The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.

Involvement of microglia in the ethanol-induced neuropathic pain-like state in the rat.

Central mechanisms of neuropathy induced by chronic ethanol treatment are almost unknown. In this study, rats were treated with ethanol-diet for 72 days. Mechanical hyperalgesia was observed during ethanol consumption, even after ethanol withdrawal. Under these conditions, a microglial marker ionized calcium-binding adaptor molecule 1-, but not a neuron marker microtuble associated protein-2-, like immunoreactivies were increased in the rat spinal cord. Furthermore, hypertrophy of microglia was clearly observed following chronic ethanol consumption. These findings support the idea that the activation and hypertrophy of microglia in the spinal cord may be, at least in part, associated with in the induction of ethanol-dependent neuropathic pain-like state.

Involvement of mGluR5 in the ethanol-induced neuropathic pain-like state in the rat.

Alcohol neuropathy has been thought to involve decreased nerve function following chronic ethanol consumption. However, there is no reliably successful therapy, largely due to a lack of understanding of the central underlying mechanisms. The aim of this study was to investigate the mechanisms that contribute to the neuropathic pain-like state induced by chronic ethanol treatment in rats. Rats were chronically treated with ethanol diet (1.25-5% of ethanol) for over 70 days. Mechanical hyperalgesia was observed during ethanol consumption and even after ethanol withdrawal. Under these conditions, an immunohistochemical study showed an increase in metabotropic glutamate receptor 5 (mGluR5) immunoreactivity in the superficial spinal dorsal horn of chronic ethanol-fed rats. Furthermore, immunoblot analysis revealed that the protein level of mGluR5 was clearly increased following chronic ethanol consumption. These findings support the idea that the increased levels of mGluR5 in the spinal cord may be, at least in part, involved in the induction of ethanol-dependent neuropathic pain-like state.

Alcoholic neuropathy.

PURPOSE OF REVIEW: The concept of alcoholic neuropathy has been obscured because of an often undetected or overestimated influence of thiamine deficiency. We describe clinicopathologic features of alcoholic neuropathy, taking the effect of thiamine status into consideration, and recent progress associated with the pathogenesis. RECENT FINDINGS: Clinical features of alcoholic neuropathy without thiamine deficiency are characterized by slowly progressive, sensory-dominant symptoms. Superficial sensation is predominantly impaired and painful symptoms are the major complaint. Pathologic features are characterized by small-fiber-predominant axonal loss. In contrast, the clinicopathologic features of alcoholic neuropathy with concomitant thiamine deficiency are variable, constituting a spectrum ranging from a picture of a pure form of alcoholic neuropathy to a presentation of nonalcoholic thiamine-deficiency neuropathy. One possible mediator of the direct neurotoxic effects among the metabolites of ethanol is acetaldehyde. Axonal transport and cytoskeletal properties are impaired by ethanol exposure. Protein kinase A and protein kinase C may also play a role in the pathogenesis, especially in association with painful symptoms. SUMMARY: Nutritional deficiency as well as the direct neurotoxic effects of ethanol or its metabolites can cause alcoholic neuropathy. Although clinicopathologic features of the pure form of alcoholic neuropathy are uniform, they show extensive variation when thiamine deficiency is present.

Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosis.

Alcohol misusers frequently have difficulties in gait, and various muscle symptoms such as cramps, local pain and reduced muscle mass. These symptoms are common in alcoholic patients and have previously been ascribed as neuropathological in origin. However, biochemical lesions and/or the presence of a defined myopathy occur in alcoholics as a direct consequence of alcohol misuse. The myopathy occurs independently of peripheral neuropathy, malnutrition and overt liver disease. Chronic alcoholic myopathy is characterized by selective atrophy of Type II fibres and the entire muscle mass may be reduced by up to 30%. This myopathy is arguably the most prevalent skeletal muscle disorder in the Western Hemisphere and occurs in approximately 50% of alcohol misusers. Alcohol and acetaldehyde are potent inhibitors of muscle protein synthesis, and both contractile and non-contractile proteins are affected by acute and chronic alcohol dosage. Muscle RNA is also reduced by mechanisms involving increased RNase activities. In general, muscle protease activities are either reduced or unaltered, although markers of muscle membrane damage are increased which may be related to injury by reactive oxygen species. This supposition is supported by the observation that in the UK, alpha-tocopherol status is poor in myopathic alcoholics. Reduced alpha-tocopherol may pre-dispose the muscle to metabolic injury. However, experimental alpha-tocopherol supplementation is ineffective in preventing ethanol-induced lesions in muscle as defined by reduced rates of protein synthesis and in Spanish alcoholics with myopathy, there is no evidence of impaired alpha-tocopherol status. In conclusion, by a complex series of mechanisms, alcohol adversely affects skeletal muscle. In addition to the mechanical changes to muscle, there are important metabolic consequences, by virtue of the fact that skeletal muscle is 40% of body mass and an important contributor to whole-body protein turnover.

Monoaminergic changes associated with audiogenic seizures in ethanol-dependent rats.

1. A previous report demonstrated the efficacy of combining dopaminergic and serotonergic agonists in suppressing audiogenic seizures induced in ethanol-dependent rats undergoing withdrawal. Moreover, an increase in dopamine and a reduction in serotonin levels in the striatum were associated with such seizures. 2. The present study was designed to examine neurochemical changes in the striatum associated with repeated episodes of ethanol withdrawal seizures in untreated ethanol-dependent rats as well as in those treated with amphetamine and fenfluramine in combination. 3. Ethanol-dependent rats undergoing audiogenic seizures exhibited an increase in striatal dopamine and a reduction in striatal serotonin as compared to control and ethanol-dependent rats not undergoing seizures. Amphetamine and fenfluramine in combination effectively suppressed the audiogenic seizures by reversing the neurochemical changes in the striatum in ethanol-dependent rats. However, increased dopamine but decreased serotonin levels in the striatum were observed in rats undergoing one episode of ethanol withdrawal, but not in those experiencing multiple episodes of ethanol withdrawal. 4. Thus, alterations in striatal dopamine and serotonin levels were, at best, necessary but not sufficient to predispose audiogenic seizure susceptibility in ethanol-dependent rats.

Impaired stimulation of intestinal glucose absorption by portal insulin via hepatoenteral nerves in chronically ethanol-intoxicated rats.

In the isolated, jointly perfused small intestine and liver of rats insulin, infused into the portal vein, induced an increase in intestinal glucose absorption via hepatoenteral cholinergic nerves. The possible loss of function of these nerves due to ethanol-induced neuropathy was investigated with 6 weeks ethanol-fed rats. Portal insulin or arterial carbachol failed to increase intestinal glucose absorption but cAMP still did so. The intact stimulatory effect of cAMP indicated an undisturbed capacity of the enterocytes. The loss of action of portal insulin and of arterial carbachol can be explained by the impairment of the hepatoenteral nerves in line with an ethanol-induced neuropathy.