The role of diet and non-pharmacologic supplements in the treatment of chronic neuropathic pain: A systematic review.

BACKGROUND/IMPORTANCE: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases. OBJECTIVE: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults. EVIDENCE REVIEW: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non-pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence. FINDINGS: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy-induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS-I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N-acetyl-cysteine (2), acetyl-l-carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha-lipoic acid (1), l-carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha-lipoic acid (5 studies), vitamin B12 (3), acetyl-l-carnitine (3), vitamin E (1), vitamin D (2), and a low-fat plant-based diet (1). Vitamin C was studied to treat CRPS-I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies. CONCLUSIONS: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N-acetyl-cysteine, l-carnosine, crocin, and magnesium is warranted. Acetyl-l-carnitine was found to be likely ineffective or harmful. Alpha-lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha-lipoic acid, acetyl-l-carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS-I also seems promising. Further research is warranted to confirm these findings.

Combined Rehabilitation with Alpha Lipoic Acid, Acetyl-L-Carnitine, Resveratrol, and Cholecalciferolin Discogenic Sciatica in Young People: A Randomized Clinical Trial.

Background and Objectives: In the Western world, back pain and sciatica are among the main causes of disability and absence from work with significant personal, social, and economic costs. This prospective observational study aims to evaluate the effectiveness of a rehabilitation program combined with the administration of Alpha Lipoic Acid, Acetyl-L-Carnitine, Resveratrol, and Cholecalciferol in the treatment of sciatica due to herniated discs in young patients in terms of pain resolution, postural alterations, taking painkillers, and quality of life. Materials and Methods: A prospective observational study was conducted on 128 patients with sciatica. We divided the sample into 3 groups: the Combo group, which received a combination of rehabilitation protocol and daily therapy with 600 mg Alpha Lipoic Acid, 1000 mg Acetyl-L-Carnitine, 50 mg Resveratrol, and 800 UI Cholecalciferol for 30 days; the Reha group, which received only a rehabilitation protocol; and the Supplement group, which received only oral supplementation with 600 mg Alpha Lipoic Acid, 1000 mg Acetyl-L-Carnitine, 50 mg Resveratrol, and 800 UI Cholecalciferol. Clinical assessments were made at the time of recruitment (T0), 30 days after the start of treatment (T1), and 60 days after the end of treatment (T2). The rating scales were as follows: the Numeric Rating Scale (NRS); the Oswestry Disability Questionnaire (ODQ); and the 36-item Short Form Health Survey (SF-36). All patients also underwent an instrumental stabilometric evaluation. Results: At T1, the Combo group showed statistically superior results compared to the other groups for pain (p < 0.05), disability (p < 0.05), and quality of life (p < 0.05). At T2, the Combo group showed statistically superior results compared to the other groups only for pain (p < 0.05) and quality of life (p < 0.05). From the analysis of the stabilometric evaluation data, we only observed a statistically significant improvement at T2 in the Combo group for the average X (p < 0.05) compared to the other groups. Conclusions: The combined treatment of rehabilitation and supplements with anti-inflammatory, pain-relieving, and antioxidant action is effective in the treatment of sciatica and can be useful in improving postural stability.

Anti-Hyperalgesic Efficacy of Acetyl L-Carnitine (ALCAR) Against Visceral Pain Induced by Colitis: Involvement of Glia in the Enteric and Central Nervous System.

The management of abdominal pain in patients affected by inflammatory bowel diseases (IBDs) still represents a problem because of the lack of effective treatments. Acetyl L-carnitine (ALCAR) has proved useful in the treatment of different types of chronic pain with excellent tolerability. The present work aimed at evaluating the anti-hyperalgesic efficacy of ALCAR in a model of persistent visceral pain associated with colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) injection. Two different protocols were applied. In the preventive protocol, ALCAR was administered daily starting 14 days to 24 h before the delivery of DNBS. In the interventive protocol, ALCAR was daily administered starting the same day of DNBS injection, and the treatment was continued for 14 days. In both cases, ALCAR significantly reduced the establishment of visceral hyperalgesia in DNBS-treated animals, though the interventive protocol showed a greater efficacy than the preventive one. The interventive protocol partially reduced colon damage in rats, counteracting enteric glia and spinal astrocyte activation resulting from colitis, as analyzed by immunofluorescence. On the other hand, the preventive protocol effectively protected enteric neurons from the inflammatory insult. These findings suggest the putative usefulness of ALCAR as a food supplement for patients suffering from IBDs.

The effects of two different antioxidant combinations on sperm parameters.

BACKGROUND: Studies demonstrate that getting antioxidants in the course of treatment has a positive impact beneficial effect on fertility, especially on the quality of sperm. Because of that reason antioxidants are recommended as a potentially influential treatment for infertility in men. However, it is argued that this treatment is not based on sufficient evidence and has no effect on the rate of healthy pregnancy. OBJECTIVE: In this study, two different antioxidant combinations with different doses and contents were evaluated in terms of their effect on sperm parameters. MATERIALS/METHODS: A total of 122 patients diagnosed with idiopathic infertility were enrolled in our multicenter study. The patients were divided into two different groups: The first group used a combination 2 × 1 sachet form (l-carnitine 1 g, acetyl-l-carnitine 0.5 g, fructose 1 g, citric acid 0.50 mg, selenium 50 µg, coenzyme Q10 20 mg, vitamin C 90 mg, zinc 10 mg, folic acid 200 µg, and vitamin B12 1.5 µg) and the second group used a combination tablets form 2 × 1 (l-carnitine 500 mg, selenium 50 µg, coenzyme Q10 20 mg, vitamin C 60 mg, zinc 15 mg, folic acid 400 µg, vitamin E, and ginseng 15 µg) for 6 months. The total semen volume, the total sperm number, sperm concentration, sperm motility, and lastly morphological findings of the patients were compared at the end of 6 months. RESULTS: The mean age of the patients participating in the study was 30.8 ± 6.05 years. No significant difference was found between the two groups in terms of baseline sperm count. There was a significant difference between the baseline and sixth-month values of the patients using both combinations. However, no significant statistical difference was found between the groups according to the sixth-month data. The combinations of both antioxidants had a positive effect on sperm parameters, and the use of different doses and contents had a similar effect. CONCLUSION: Both antioxidants respectively had a positive effect on sperm parameters and also the use of different doses and contents had a similar effect.

Ameliorative Effect of Acetyl L-carnitine in Alzheimer's Disease via Downregulating of Homocysteine Levels in Hyperhomocysteinemia Induced Cognitive Deficit in Mouse Model.

AIMS: The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. BACKGROUND: Alzheimer's disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. OBJECTIVE: The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer's disease (AD) in the mouse model. MATERIALS AND METHODS: The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+ SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. RESULTS: Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. CONCLUSION: ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.

Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC FC) in the treatment of neuropathies secondary to rheumatic diseases.

BACKGROUND: The neurologic complications of rheumatic diseases (RDs) are highly variable, and their manifestations are linked to the pathogenesis and clinical phenotype of the specific RDs. In rheumatoid arthritis, for example, the peripheral nervous system is most commonly involved and mononeuritis multiplex, nerve entrapment and vasculitic sensorimotor neuropathies are not uncommon. Often the therapy for these disorders is not easy and is characterized by the use of different drugs. Palmitoylethanolamide (PEA) has been tested in a wide variety of animal models and has been evaluated in several clinical studies for nerve compression syndromes, demonstrating that PEA acts as an effective and safe analgesic compound. Acetyl-L-Carnitine (ALC) has also been shown to be an effective and safe treatment in painful peripheral neuropathy. In the last years the synergistic effect between PEA and ALC has been demonstrated. The aim of our study was to evaluate the efficacy of supplementation of standard therapy (STh) with Kalanit® (Chiesi Italia Spa; Parma, Italy) in patients with peripheral neuropathy secondary to RDs. METHODS: Patients at the time of enrollment were affected by RDs with neuropathy from <12 months, documented by electromyography. The analyzed patients were treated with the STh chosen according to their rheumatic disease (RA or SpA) and for their neuropathy (e.g. analgesic, NSAIDs, pregabalin or gabapentin) as per clinical practice. The sample was divided into 2 groups: group 1, patients treated with STh, to which a fixed combination of PEA (600 mg) + ALC (500 mg) (Kalanit®) was added twice a day for 2 weeks and then once a day for 6 months; group 2, patients treated only with STh. Each patient underwent clinical evaluations and questionnaires were administered in order to evaluate their neuropathy and the efficacy of the therapy. RESULTS: In group 1, 18 patients suffering from sciatic pain, 16 patients from carpal tunnel syndrome and 8 patients with peripheral neuropathy of the lower limbs were included and PEA + ALC FC was added to STh. These patients were compared with patients from group 2, who had the same pathology and demographic characteristics: 20 patients with sciatic pain, 15 with carpal tunnel syndrome and 5 with peripheral neuropathy of the lower limbs, respectively; this group was treated with STh only. Patients treated with PEA + ALC FC had a significant improvement in pain VAS compared to patients treated with group 2 in all the diseases analyzed (P value: sciatic pain 0.032, carpal tunnel syndrome 0.025 and lower limbs neuropathy 0.041). Patients in group 1 showed a significant improvement compared to patients treated in group 2 also from a specific score. Specifically, LBP-IQ showed significant improvement in group one (P value: 0.031), as did CHFD (P=0.011) and NPQ (P=0.025). CONCLUSIONS: The synergistic effect of PEA and ALC seems to have a further advantage in the treatment of this type of pathology, including the anti-inflammatory effect but also in terms of therapy optimization and therefore of better adherence to treatments. Our study shows that it is important to identify the type of pain to follow an accurate diagnostic algorithm, considering the clinical characteristics of the patient and carefully evaluate the indication, preferring a multimodal approach.

Acetyl-L-carnitine for the treatment of diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common and severe complication that affects 50% of people with diabetes. Painful DPN is reported to occur in 16% to 24% of people with diabetes. A complete and comprehensive management strategy for the prevention and treatment of DPN, whether painful or not, has not yet been defined.Research into treatment for DPN has been characterised by a series of failed clinical trials, with few noteworthy advances. Strategies that support peripheral nerve regeneration and restore neurological function in people with painful or painless DPN are needed. The amino acid acetyl-L-carnitine (ALC) plays a role in the transfer of long-chain fatty acids into mitochondria for ß-oxidation. ALC supplementation also induces neuroprotective and neurotrophic effects in the peripheral nervous system. Therefore, ALC supplementation targets several mechanisms relevant to potential nerve repair and regeneration, and could have clinical therapeutic potential. There is a need for a systematic review of the evidence from clinical trials. OBJECTIVES: To assess the effects of ALC for the treatment of DPN. SEARCH METHODS: On 2 July 2018, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We checked references, searched citations, and contacted study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of ALC compared with placebo, other therapy, or no intervention in the treatment of DPN. Participants could be of any sex and age, and have type 1 or type 2 diabetes mellitus, of any severity, with painful or painless DPN. We accepted any definition of minimum criteria for DPN, in accordance with the Toronto Consensus. We imposed no language restriction.Pain was the primary outcome, measured as the proportion of participants with at least 30% (moderate) or 50% (substantial) decrease in pain over baseline, or as the score on a visual analogue scale (VAS) or Likert scale for pain. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: We included four studies with 907 participants, which were reported in three publications. Three trials studied ALC versus placebo (675 participants); in one trial the dose of ALC was 2000 mg/day, and in the other two trials, it was 1500 mg/day or 3000 mg/day. The fourth trial studied ALC 1500 mg/day versus methylcobalamin 1.5 mg/day (232 participants). The risk of bias was high in both trials of different ALC doses and low in the other two trials.No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief. ALC reduced pain more than placebo, measured on a 0- to 100-mm VAS (MD -9.16, 95% CI -16.76 to -1.57; three studies; 540 participants; P = 0.02; I² = 56%; random-effects; very low-certainty evidence; a higher score indicating more pain). At doses of 1500 mg/day or less, the VAS score after ALC treatment was little different from placebo (MD -0.05, 95% CI -10.00 to 9.89; two studies; 159 participants; P = 0.99; I² = 0%), but at doses greater than 1500 mg/day, ALC reduced pain more than placebo (MD -14.93, 95% CI -19.16 to -10.70; three studies; 381 participants; P < 0.00001; I² = 0%). This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.Two placebo-controlled studies reported that vibration perception improved after 12 months. We graded this evidence as very low certainty, due to inconsistency and a high risk of bias, as the trial authors did not provide any numerical data. The placebo-controlled studies did not measure functional impairment and disability scores. No study used validated symptom scales. One study performed sensory testing, but the evidence was very uncertain.The fourth included study compared ALC with methylcobalamin, but did not report effects on pain. There was a reduction from baseline to 24 weeks in functional impairment and disability, based on the change in mean Neuropathy Disability Score (NDS; scale from zero to 10), but there was no important difference between the ALC group (mean score 1.66 ± 1.90) and the methylcobalamin group (mean score 1.35 ± 1.65) groups (P = 0.23; low-certainty evidence).One placebo-controlled study reported that six of 147 participants in the ALC > 1500 mg/day group (4.1%) and two of 147 participants in the placebo group (1.4%) discontinued treatment because of adverse events (headache, facial paraesthesia, and gastrointestinal disorders) (P = 0.17). The other two placebo-controlled studies reported no dropouts due to adverse events, and more pain, paraesthesia, and hyperaesthesias in the placebo group than the 3000 mg/day ALC group, but provided no numerical data. The overall certainty of adverse event evidence for the comparison of ALC versus placebo was low.The study comparing ALC with methylcobalamin reported that 34/117 participants (29.1%) experienced adverse events in the ALC group versus 33/115 (28.7%) in the methylcobalamin group (P = 0.95). Nine participants discontinued treatment due to adverse events (ALC: 4 participants, methylcobalamin: 5 participants), which were most commonly gastrointestinal symptoms. The certainty of the adverse event evidence for ALC versus methylcobalamin was low.Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer. AUTHORS' CONCLUSIONS: We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months' treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty. Data on functional and sensory impairment and symptoms are lacking, or of very low certainty. The evidence on adverse events is too uncertain to make any judgements on safety.

Integrative neuromuscular medicine: Neuropathy and neuropathic pain: Consider the alternatives.

Complementary and alternative treatment modalities are commonly utilized by patients for neuropathy and neuropathic pain due to perceived lack of benefit from conventional medical treatment. As the association between metabolic syndrome and neuropathy is increasingly recognized, diet and lifestyle interventions are becoming important components in the management of neuropathy. Progress in the understanding of the gut-immune interaction highlights the role the gut microbiome and inflammation plays in the modulation of neuropathy and neuropathic pain. Evidence for nutritional interventions, exercise, supplements, acupuncture, and mindfulness-based practices in the treatment of neuropathic pain is encouraging. This article reviews the available evidence to support the safe use of complementary and alternative treatments for commonly encountered conditions associated with neuropathy and neuropathic pain. Muscle Nerve 60: 124-136, 2019.

Acetyl-L-carnitine as a putative candidate for the treatment of stress-related psychiatric disorders: Novel evidence from a zebrafish model.

Stress-related psychiatric disorders are mental conditions that affect mood, cognition and behavior and arise because of the impact of prolonged stress on the central nervous system (CNS). Acetyl-L-carnitine (ALC) is an acetyl ester of L-carnitine that easily crosses the blood-brain barrier and was recently found to be decreased in patients with major depressive disorder. ALC plays a role in energy metabolism and is widely consumed as a nutritional supplement to improve physical performance. In this study, our objective was to evaluate the effects of ALC treatment (0.1 mg/L, 10 min) for 7 days on behavior and oxidative stress in zebrafish subjected to unpredictable chronic stress (UCS) protocol. Behavioral outcomes were assessed in the novel tank test, and parameters of oxidative status (lipid peroxidation and antioxidant defenses) were evaluated in the brain using colorimetric methods. According to our previous findings, UCS increased anxiety-like behavior and lipid peroxidation, while it decreased non-protein thiol levels and superoxide dismutase activity. However, ALC reversed the anxiety-like behavior and oxidative damage in stressed animals, while it was devoid of effect in control animals. Although our data reinforce the neuroprotective potential of ALC in the treatment of psychiatric disorders related to stress, further investigations are required to clarify its mechanisms of action and confirm its efficacy.

Acetyl-L-Carnitine to Enhance Nerve Regeneration in Carpal Tunnel Syndrome: A Double-Blind, Randomized, Controlled Trial.

BACKGROUND: Carpal tunnel syndrome is very common. Although surgery is effective in mild and moderate cases, recovery is often incomplete in severe cases. Therefore, adjuvant therapy to improve nerve regeneration in those patients is much needed. Acetyl-L-carnitine has been shown to be effective in other neuropathies. The goal of this study is to test the hypothesis that acetyl-L-carnitine can promote nerve regeneration and improve function in patients with severe carpal tunnel syndrome. METHODS: In this proof-of-principle, double-blind, randomized, placebo-controlled trial, adults with severe carpal tunnel syndrome were randomized to receive 3000 mg/day of acetyl-L-carnitine orally or placebo following carpal tunnel release surgery for 2 months. Outcomes were assessed at baseline and at 3, 6, and 12 months postoperatively. Symptom severity and functional outcomes were assessed using the Boston Carpal Tunnel Questionnaire and a wide range of physiologic and functional outcome measures. Patient safety was monitored by physical examination, blood work, and serum drug levels. The outcomes were analyzed using repeated measure two-way analysis of variance. RESULTS: Twenty patients with similar baseline characteristics were assigned randomly to the treatment or placebo group in a 1:1 ratio. Sixty percent were women with a mean age ± SD of 59 ± 2. The treatment was safe with no major adverse events reported. Although patients in both groups showed improvements postoperatively, there was no significant difference in any of the outcome measures between the groups. CONCLUSION: Although acetyl-L-carnitine was well tolerated, it did not improve nerve regeneration or functional recovery in patients with severe carpal tunnel syndrome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

[Effects of acetyl-L-carnitine on the recovery of hindlimb movement afterspinal cord injury in rats and its mechamism].

OBJECTIVE: To observe the effects of different doses of acetyl-L-carnitine (ALC) on hindlimb motor function and spinal cord tissue structure in rats with spinal cord injury. The study will provide theoretical and experimental evidences for acetyl-L-carnitine's clinical treatment. METHODS: Fifty-five SD rats aged 8-10 weeks were randomly divided into high, medium and low-dose drug intervention (SCI + ALC) group, injury group (SCI) and sham group for behavioral evaluation, MAD and SOD detection, as well as HPLC detection and HE staining. BBB scores and Rivlin experiments were performed to evaluate hindlimb motor function in each group. The morphology and structure of spinal cord tissue was detected by HE staining. Another 9 rats were randomly divided into Sham group, SCI group and ALC group for TUMEL detection of apoptosis. RESULTS: The BBB scores of the high, medium, and low dose SCI+ALC groups were significantly higher than those in the SCI group. The medium and high-dose ALC groups had significant differences (P＜0.01), and the hindlimb motor function was significantly improved in rats. The maximum tilt angle of the Rivlin experiment was observed. The SCI+ALC group had a significantly increased angle compared with the SCI group (P＜0.05), the medium and high-dose ALC group had a significant difference (P＜0.01). Compared with the SCI group, the tissue structure of ALC high-dose group was improved significantly, the number of inflammatory cells and red blood cells was decreased, and the nucleolus of the nerve cells was unclear. The SOD activity of the SCI+ALC group was significantly higher than that of the SCI group, while the MDA content was significantly decreased(P＜0.05), the middle and high dose ALC groups were significantly different (P＜0.01). HPLC chromatogram showed that the SCI+ALC fresh serum sample and the ALC standard solution had the same absorption spectrum at 260 nm, while the Sham group and SCI group serum samples did not show spectral values there, which indicated that the same substance as the standard existed in the sample of SCI+ALC group. TUNEL staining showed that the apoptosis signal was occasionally seen in the sham group, and the apoptosis signal was significantly decreased in the ALC high-dose group compared with the SCI group(P＜0.05). CONCLUSION: ALC can promote the recovery of hindlimb motor function in rats with spinal cord injury, inhibit oxidative stress and apoptosis, and repair the damaged spinal cord tissue.

The possible anti-apoptotic and antioxidant effects of acetyl l-carnitine as an add-on therapy on a relapsing-remitting model of experimental autoimmune encephalomyelitis in rats.

Multiple sclerosis (MS) is a progressive inflammatory autoimmune demyelinating disease of the brain and spinal cord. Glucocorticoids (GCs) are the standard treatment of MS, however they have several drawbacks like oxidative stress and apoptosis. This study was designed to evaluate some possible antioxidant, anti-apoptotic and immune modulatory effects of Acetyl-l-carnitine (ALCAR) when used either alone or as an add-on therapy with dexamethasone for treatment of a relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) as a model of MS. This experiment was performed on 50 female Sprague Dawley rats divided into; normal control group, untreated EAE group, EAE group treated by dexamethasone, EAE group treated by ALCAR, and EAE group treated by both dexamethasone and ALCAR. The clinical score of the motor deficit of EAE was recorded daily. At the end of experiment, rats were sacrificed and the brain and spinal cord were processed for assessment of reduced glutathione (GSH), malondialdehyde (MDA) and caspase-3 activity. Histopathological changes and immunohistochemical expression of Bcl-2 and CD4+ T cell were carried out. Combination of both dexamethasone and ALCAR provided marked antioxidant and anti-apoptotic effects represented by significant decrease in MDA, caspase-3 and significant increase in GSH, Bcl-2 expression, and it also exhibited marked immunosuppressive effect represented by significant decrease in CD4+ T cells expression with significant improvement in clinical outcome when compared to untreated EAE group or to dexamethasone treated group. These findings pave the way for using ALCAR as an adjuvant therapy during long-term use of dexamethasone in MS.

Use of Vitamins and Dietary Supplements by Patients With Multiple Sclerosis: A Review.

Importance: Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues. Observations: Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studies may help guide clinical recommendations. Conclusions and Relevance: At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation.

Age-related defects in short-term plasticity are reversed by acetyl-L-carnitine at the mouse calyx of Held.

Hearing acuity and sound localization are affected by aging and may contribute to cognitive dementias. Although loss of sensorineural conduction is well documented to occur with age, little is known regarding short-term synaptic plasticity in central auditory nuclei. Age-related changes in synaptic transmission properties were evaluated at the mouse calyx of Held, a sign-inverting relay synapse in the circuit for sound localization, in juvenile adults (1 month old) and late middle-aged (18-21 months old) mice. Synaptic timing and short-term plasticity were severely disrupted in older mice. Surprisingly, acetyl-l-carnitine (ALCAR), an anti-inflammatory agent that facilitates mitochondrial function, fully reversed synaptic transmission delays and defects in short-term plasticity in aged mice to reflect transmission similar to that seen in juvenile adults. These findings support ALCAR supplementation as an adjuvant to improve short-term plasticity and potentially central nervous system performance in animals compromised by age and/or neurodegenerative disease.

[Using L- and acetyl-L-carnintines in combination with clomiphene citrate and antioxidant complex for treating idiopathic male infertility: a prospective randomized trial].

The most common cause of male infertility is idiopathic oligo-, and or astheno-, and /or teratozoospermia. In such cases, anti-estrogens, antioxidants (vitamins and trace elements) or carnitines are used, but the evidence on their effectiveness is inconsistent; there are currently no published studies exploring their concurrent use. AIM: To investigate the efficacy and safety of the L- and acetyl-L-carnitine complex, vitamins A, E, C, selenium, zinc and other antioxidants ("SpermActin" + "More than vitamins") in combination with clomiphene citrate (CC) in managing male idiopathic infertility in the form of oligo, and/or astheno-, and/or teratozoospermia. MATERIALS AND METHODS: The study comprised 173 men from infertile couples aged 25-45 years who were divided into two groups - the study group (n=88) and control group (n=85). All the patients were examined according to the WHO recommendations. Patients of the study group received L-carnitine fumarate (1 g), acetyl-L-carnitine (0.5 g) twice daily, a complex of vitamins and microelements and CC 25 mg twice daily orally. Patients of the control group were administered the same dosages of CC and a complex of vitamins. Ejaculate was evaluated before and after 3-4 months of treatment. Six months after the start of treatment, information about the onset or absence of pregnancy over the last six months was collected via telephone or online survey. RESULTS: Co-administration of L- and acetyl-L-carnitines concurrently with CC and antioxidant complex (vitamins and minerals) in patients with idiopathic oligo- and/or asteno- and/or teratozoospermia provides some additional positive effect on the concentration of spermatozoa, more pronounced in patients with multiple impaired semen parameters - oligoasthenoteratozoospermia, but does not improve the morphology, progressive sperm motility and pregnancy rates compared to patients receiving basic treatment.

N-Acetylcysteine Prevents Retrograde Motor Neuron Death after Neonatal Peripheral Nerve Injury.

BACKGROUND: Neuronal death may be an overlooked and unaddressed component of disability following neonatal nerve injuries, such as obstetric brachial plexus injury. N-acetylcysteine and acetyl-L-carnitine improve survival of neurons after adult nerve injury, but it is unknown whether they improve survival after neonatal injury, when neurons are most susceptible to retrograde neuronal death. The authors' objective was to examine whether N-acetylcysteine or acetyl-L-carnitine treatment improves survival of neonatal motor or sensory neurons in a rat model of neonatal nerve injury. METHODS: Rat pups received either a sciatic nerve crush or transection injury at postnatal day 3 and were then randomized to receive either intraperitoneal vehicle (5% dextrose), N-acetylcysteine (750 mg/kg), or acetyl-L-carnitine (300 mg/kg) once or twice daily. Four weeks after injury, surviving neurons were retrograde-labeled with 4% Fluoro-Gold. The lumbar spinal cord and L4/L5 dorsal root ganglia were then harvested and sectioned to count surviving motor and sensory neurons. RESULTS: Transection and crush injuries resulted in significant motor and sensory neuron loss, with transection injury resulting in significantly less neuron survival. High-dose N-acetylcysteine (750 mg/kg twice daily) significantly increased motor neuron survival after neonatal sciatic nerve crush and transection injury. Neither N-acetylcysteine nor acetyl-L-carnitine treatment improved sensory neuron survival. CONCLUSIONS: Proximal neonatal nerve injuries, such as obstetric brachial plexus injury, produce significant retrograde neuronal death after injury. High-dose N-acetylcysteine significantly increases motor neuron survival, which may improve functional outcomes after obstetrical brachial plexus injury.

Acetyl-L-carnitine (ALCAR) to enhance nerve regeneration in carpal tunnel syndrome: study protocol for a randomized, placebo-controlled trial.

BACKGROUND: Carpal tunnel syndrome (CTS) is the most common form of peripheral nerve injury, affecting approximately 3 % of the population. While surgery is effective in mild and moderate cases, nerve and functional recovery are often not complete in severe cases. Therefore, there is a need for adjuvant methods to improve nerve regeneration in those cases. Acetyl-L-carnitine (ALCAR) is involved in lipid transport, vital for mitochondrial function. Although it has been shown to be effective in various forms of neuropathies, it has not been used in traumatic or compressive peripheral nerve injury. METHODS: In this pilot study we will utilize a double-blind, randomized, placebo-controlled design. Inclusion criteria will include adult patients with severe CTS. This will be confirmed by nerve conduction studies and motor unit number estimation (MUNE). Only those with severe motor unit loss in the thenar muscles (2 standard deviations [SD] below the mean for the age group) will be included. Eligible patients will be randomized to receive 3,000 mg/day of ALCAR orally or placebo following carpal tunnel release surgery for 2 months. The primary outcome will be MUNE with supplementary secondary outcome measures that include: 1) two-point discrimination; 2) Semmes-Weinstein monofilaments for pressure sensitivity; 3) cold and pain threshold for small fiber function; 4) Boston self-assessment Carpal Tunnel Questionnaire and 5) Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire for symptom severity; and 6) Purdue Pegboard Test for hand functional performance. To follow post treatment recovery and monitor safety, patients will be seen at 3 months, 6 months and 1 year. The outcome measures will be analyzed using two-way ANOVA, with treatment assignment and time points being the independent factors. If significant associations are detected, a post hoc analysis will be completed. We aim to recruit ten patients into each of the two groups. Data from this pilot will provide the basis for power calculation for a full-scale trial. DISCUSSION: ALCAR is a physiologic peptide crucial for fatty acid transport. ALCAR has been shown to be effective in neuroprotection in the central nervous system and increase peripheral nerve regeneration. This has been applied clinically to various systemic peripheral neuropathies including diabetic neuropathy, antiretroviral toxic neuropathy, and chemotherapy-induced peripheral neuropathy. While animal evidence exists for the benefit of ALCAR in compression neuropathy, there have been no human studies to date. This trial will represent the first use of ALCAR in peripheral nerve injury/compression neuropathy. TRIAL REGISTRATION: NCT02141035 ; 20 April 2015.

Targeting neuropathic pain: consider these alternatives.

When patients with painful peripheral neuropathy fail to respond to--or are unable to tolerate--standard therapies, consider these lesser-known treatments.

Supplemental substances derived from foods as adjunctive therapeutic agents for treatment of neurodegenerative diseases and disorders.

Neurodegenerative disorders and diseases (NDDs) that are either chronically acquired or triggered by a singular detrimental event are a rapidly growing cause of disability and/or death. In recent times, there have been major advancements in our understanding of various neurodegenerative disease states that have revealed common pathologic features or mechanisms. The many mechanistic parallels discovered between various neurodegenerative diseases suggest that a single therapeutic approach may be used to treat multiple disease conditions. Of late, natural compounds and supplemental substances have become an increasingly attractive option to treat NDDs because there is growing evidence that these nutritional constituents have potential adjunctive therapeutic effects (be it protective or restorative) on various neurodegenerative diseases. Here we review relevant experimental and clinical data on supplemental substances (i.e., curcuminoids, rosmarinic acid, resveratrol, acetyl-L-carnitine, and ω-3 (n-3) polyunsaturated fatty acids) that have demonstrated encouraging therapeutic effects on chronic diseases, such as Alzheimer's disease and neurodegeneration resulting from acute adverse events, such as traumatic brain injury.

Ameliorative effect of acetyl-L-carnitine and/or nifedipine against selenite-induced cataractogenesis in young albino rats.

Free radical toxicity and calcium ion overload have been identified as the major two players in the causation of cataract. The current study was carried out to investigate the anti-cataractogenic effect of single and combined treatment with acetyl-l-carnitine and nifedipine in sodium selenite-induced cataract. Rat pups were divided into 5 groups; 1st group received intraperitoneal injection (i.p.) of saline and served as normal control, 2nd group received single subcutaneous injection of sodium selenite 30nmol/g body weight on p10 (postpartum day 10), 3rd and 4th groups received either acetyl-l-carnitine (200mg/kg, i.p.) or nifedipine (0.1mg/kg, i.p.) on p9, respectively, before the administration of sodium selenite, and the treatment continued till p14. Last group received the combined treatments of acetyl-l-carnitine and nifedipine in the same regimen. All animals were examined using a slit lamp and retroillumination then sacrificed on p30. Lenses were removed and processed for biochemical analyses, histopathological and electron microscopic examination. Selenite-treated groups showed significantly (P≤0.05) lower values of redox system components (glutathione and glutathione reductase activity) and anti-oxidant enzymes׳ activities (superoxide dismutase and catalase) along with increased lipid peroxidation that was accompanied by 100% opacified crystalline lenses (mature cataract) with abnormal structure as detected by electron microscopy. It is concluded that acetyl-l-carnitine or nifedipine was able to partially protect against selenite-induced abnormalities. While, combined treatment with acetyl-l-carnitine and nifedipine was superior to individual treatments in slowing down the development of cataract by restoring the anti-oxidant defense and mitigating lipid peroxidation in the lens and hence represents an attractive anti-cataractogenic remedy.