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.

Clinical usefulness of nutraceutics with acetyl-L-carnitine, α-lipoic acid, phosphatidylserine, curcumin, C, E and B-group vitamins in patients awaiting for carpal tunnel release during COVID-19 pandemic: a randomized controlled open label prospective study.

BACKGROUND AND AIM OF THE WORK: Carpal Tunnel Syndrome (CTS) is provoked by the compression of the median nerve, leading to nerve ischemia, endoneural edema, venous congestion, and subsequent metabolic alterations. Conservative treatments could be considered. The present study investigates the efficacy of a specific blend of a 600 mg dietary integrator composed of acetyl-L-carnitine, α-lipoic acid, phosphatidylserine, Curcumin, C, E and B1, B2, B6 and B12 vitamins in patients with mild to moderate CTS. METHODS: The present investigation involved the outpatients who were planned to undergo open surgical decompression of the median nerve awaiting surgery from June 2020 and February 2021. CTS surgery has been significantly reduced in our institutions during the COVID-19 pandemic. Patients were randomized into Group A (dietary integration 600 mg twice day for 60 days) and Group B (control group, no drug administration). Clinical and functional improvement was prospectively measured after 60 days Results: One-hundred forty-seven patients completed the study, 69 from group A and 78 from group B. BCTQ was significantly improved with the drug administration, as well as BCTQ symptoms subscale, and the pain. BCTQ function subscale and Michigan Hand Questionnaire was not significantly improved. Ten patients in group A (14.5%) declared that they didn't need further treatment. No major side effects were noticed. CONCLUSIONS: Dietary integration could be considered as an option in patients who could not undergo surgery. Symptoms and pain could improve, but surgery remains the gold standard for recovery of function in mild to moderate CTS.

A comparative study of acetyl-l-carnitine and caloric restriction impact on hippocampal autophagy, apoptosis, neurogenesis, and astroglial function in AlCl3-induced Alzheimer's in rats.

Alzheimer's disease (AD) is a worldwide chronic progressive neurodegenerative disease. We aimed to investigate and compare the neuroprotective impact of acetyl-l-carnitine and caloric restriction (CR) on AlCl3-induced AD to explore the pathogenesis and therapeutic strategies of AD. Sixty-seven adult male Wistar rats were allocated into Control, AlCl3, AlCl3-acetyl-l-carnitine, and AlCl3-CR groups. Each of AlCl3 and acetyl-l-carnitine were given by gavage in a daily dose of 100 mg/kg and CR was conducted by giving 70% of the daily average caloric intake of the control group. Rats were subjected to behavioral assessment using open field test, Y maze, novel object recognition test and passive avoidance test, biochemical assay of serum phosphorylated tau (pTau), hippocampal homogenate phosphorylated adenosine monophosphate-activated protein kinase, Beclin-1, Bcl-2-associated X protein, and B cell lymphoma 2 (Bcl2) as well as hippocampal Ki-67 and glial fibrillary acidic protein immunohistochemistry. AlCl3-induced cognitive and behavioral deficits coincident with impaired autophagy and enhanced apoptosis associated with defective neurogenesis and defective astrocyte activation. Acetyl-l-carnitine and CR partially protect against AlCl3-induced behavioral, cognitive, biochemical, and histological changes, with more ameliorative effect of acetyl-l-carnitine on hippocampal apoptotic markers, and more obvious behavioral and histological improvement with CR.

Inadvertent intrathecal drug injection while treating low back pain: a case report and review of the literature.

BACKGROUND: Undesired intrathecal injections represent an important subset of medical errors, albeit rare. Clinical effects depend on the type and concentration of drug(s) injected. Here we report on the case of a healthy woman with persistent low back pain, treated with a paravertebral injection of lidocaine, thiocolchicoside, and L-acetylcarnitine at an orthopedic practice. CASE REPORT: A 42-year-old Caucasian woman, with no relevant past medical history, received a lumbar paravertebral injection of lidocaine, thiocolchicoside, and L-acetylcarnitine for persistent low back pain. Approximately 30 minutes after injection, she experienced quick neurological worsening. Upon arrival at the Emergency Department, she was comatose, with fixed bilateral mydriasis, trismus, and mixed acidosis; seizures ensued in the first hours; slow progressive amelioration was observed by day 6; retrograde amnesia was the only clinical relevant remaining symptom by 6 months. CONCLUSIONS: To our knowledge, this is the first reported case of inadvertent intrathecal thiocolchicoside injection in an adult patient, as well as the first in the neurosurgical literature. Our experience suggests that injection therapy for low back pain should be administered in adequate settings, where possible complications may be promptly treated.

Clinical Evidence of Acetyl-L-Carnitine Efficacy in the Treatment of Acute Ischemic Stroke: A Pilot Clinical Trial.

Background: This study was undertaken to evaluate the influence of oral Acetyl-L-carnitine (ALC) in patients with acute ischemic stroke. Methods: Sixty-nine cases with acute ischemic stroke with the onset of symptoms less than 24 hours not candidates for reperfusion therapy were randomly assigned to either the ALC group (1000 mg three times per day for three consecutive days) or the matching placebo group. The study outcomes based on intention-to-treat criteria included the change in the modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS) score from baseline to day 90, as well as the change in serum levels of the inflammatory and oxidative stress biomarkers over the 3-day treatment protocol. Results: The NIHSS score and mRS score on day 90 were improved by 5.82 and 0.94 scores, respectively, in the ALC-treated group compared to 2.83 and 0.11 scores, respectively, in the placebo-treated group, which demonstrated the superiority of ALC relative to placebo. By using the multivariable analysis after adjusting for other variables in the model, compared to the group treated with placebo, patients in the ALC group had lower NIHSS score (ß: -2.40, 95% CI: -0.69, -4.10 (p = 0.007)) and mRS score (ß: -1.18, 95% CI: -0.52, -1.84 (p = 0.001)) 90 days after the intervention. The percentage of patients with a favourable functional outcome at day 90, defined as mRS scores of 0 or 1, was significantly higher in the ALC group in comparison to the placebo group (52.9% versus 28.6%). Further, over the 3-day treatment protocol, in the patients receiving ALC, the serum levels of proinflammatory biomarkers, including soluble intercellular adhesion molecule-1 (sICAM-1), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and neuron-specific enolase (NSE), showed a significant decrease, while the serum levels of antioxidant biomarkers, including glutathione peroxidase (GPx), superoxide dismutase (SOD), and total antioxidant capacity (TAC), as well as the total L-carnitine's level showed a significant increase compared to those in patients receiving placebo indicating significant alteration. Conclusions: Although preliminary, these results suggested that ALC administration during the acute phase of ischemic stroke might be helpful in improving functional and neurological outcomes that are probably linked to its anti-inflammatory and antioxidant properties. Trial Registration. This trial is registered with IRCT20150629022965N17 at Iranian Registry of Clinical Trials (registration date: 25/07/2018).

Acetyl-L-carnitine improves erectile function in bilateral cavernous nerve injury rats via promoting cavernous nerve regeneration.

BACKGROUND: Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair. OBJECTIVES: To investigate the effect and potential mechanism of ALCAR in the treatment of NED. MATERIALS AND METHODS: Thirty-two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower-dose ALCAR (50 mg/kg/day) group, BCNI + higher-dose (100 mg/kg/day) group, and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro. RESULTS: We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen content in the corpus cavernosum in the BCNI group. The expressions of fibrosis markers transforming growth factor-beta (TGF-ß), connective tissue growth factor (CTGF), and Smad 2/3 were significantly up-regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher-dose ALCAR. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate pathway (cGMP) was promoted and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased neuronal nitric oxide synthase (nNOS) and down-regulated tyrosine hydroxylase (TH). In vitro, ALCAR promoted the migration and proliferation of SC and increased the expression of 22-kD peripheral myelin protein and nerve growth factor (NGF). Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site. DISCUSSION AND CONCLUSION: ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED.

Acetyl-L-carnitine in chronic pain: A narrative review.

Acetyl-L-carnitine (ALC) is an endogenous molecule that not only plays a role in energy metabolism, but also has antioxidant properties, protects from oxidative stress, modulates brain neurotransmitters such as acetylcholine, serotonin and dopamine, and acts on neurotrophic factors such as nerve growth factor (NGF) and metabotropic glutamate (mGlu) receptors by means of epigenetic mechanisms. Importantly, it induces mGlu2 expression at nerve terminals, thus giving rise to analgesia and preventing spinal sensitisation. It has also been found to have even long-term neurotrophic and analgesic activity in experimental models of chronic inflammatory and neuropathic pain. The aim of this narrative review is to summarise the current evidence regarding the use of ALC in patients with chronic pain, and cognitive and mood disorders, and investigate the rationale underlying its use in patients with fibromyalgia syndrome, which is characterised by nociplastic changes that increase the sensitivity of the nervous system to pain.

Acetyl-L-Carnitine Ameliorates Metabolic and Endocrine Alterations in Women with PCOS: A Double-Blind Randomized Clinical Trial.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder and the main cause of infertility in women of reproductive age. Affected women suffer from insulin resistance and present with an intense stress response. Treatment with insulin sensitizers alone and in combination is used to ameliorate the signs and symptoms associated with the disease. This study was designed to compare the endocrine and metabolic parameters as well as subjective and objective measures of stress in women with PCOS before and after treatment with acetyl-L-carnitine (ALC) and metformin plus pioglitazone. METHODS: A total of 147 women with PCOS were randomly assigned into two groups: the combo group (n = 72) received a combination of metformin, pioglitazone, and ALC (500 mg, 15 mg, and 1500 mg, respectively), twice daily; the Met + Pio group (n = 75) received metformin plus pioglitazone (500 mg, 15 mg, respectively) and placebo (citric acid plus calcium carbonate), twice daily for 12 weeks. Medications were discontinued when pregnancy was confirmed. The Perceived Stress Scale (PSS14) and Profile of Mood States (POMS) were employed as subjective measures of stress. The endocrine and metabolic functions of women with PCOS were assessed by measuring insulin, leutinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and adiponectin levels in fasting blood samples. Insulin resistance was calculated by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). RESULTS: Women at baseline had significantly elevated circulating concentration of insulin and low level of adiponectin. Treatment decreased insulin in both groups; however, the combo group showed a significant decrease (p = 0.001). Serum adiponectin level was raised significantly after treatment in both groups (p < 0.001). HOMA-IR also decreased in both groups (both p < 0.001). Testosterone, FSH, and LH significantly improved in both groups. LH also decreased in both groups; however, the change was significant only in the combo (metformin plus pioglitazone plus ALC) group (p = 0.013). Interestingly, there was a significant improvement in body circumference (p < 0.001) in the combo group. The PSS scores of the patients improved significantly (p < 0.001) in the combo group. Interestingly, regular menstrual cycles were found (97.2%) in the carnitine group, but in only 12.9% of the other group. CONCLUSION: We conclude that addition of ALC therapy is superior to metformin plus pioglitazone in ameliorating insulin resistance, polycystic ovaries, menstrual irregularities, and hypoadiponectinemia in women with PCOS. TRIAL REGISTRATION: Trial registration: clinicalTrial.gov NCT04113889. Registered 3 October, 2019. https://clinicaltrials.gov/ct2/show/NCT04113889 .

Effect of Ultra-Micronized-Palmitoylethanolamide and Acetyl-l-Carnitine on Experimental Model of Inflammatory Pain.

Palmitoylethanolamide (PEA), a fatty acid amide, has been widely investigated for its analgesic and anti-inflammatory properties. The ultra-micronized formulation of PEA (um-PEA), that has an enhanced rate of dissolution, is extensively used. Acetyl-l-carnitine (LAC), employed for the treatment of neuropathic pain in humans, is able to cause analgesia by up-regulating type-2 metabotropic glutamate (mGlu2) receptors. In the present study, we tested different associations of um-PEA, LAC and non-micronized PEA (non-m-PEA) in a rat model of carrageenan (CAR)-induced paw edema. Intraplantar injection of CAR into the hind paw of animals caused edema, thermal hyperalgesia, accumulation of infiltrating inflammatory cells and augmented myeloperoxidase (MPO) activity. All these parameters were decreased in a significantly manner by oral administration of a compound constituted by a mixture of um-PEA and LAC in relation 1:1 (5 mg/kg), but not with the association of single compounds administered one after the other. These findings showed the superior anti-inflammatory and anti-nociceptive action displayed by oral administration of um-PEA and LAC versus LAC plus, separate but consecutive, um-PEA in the rat paw CAR model of inflammatory pain.

Anti-Inflammatory and Antioxidant Effects of Acetyl-L-Carnitine on Atherosclerotic Rats.

BACKGROUND The purpose of the present study was to evaluate the regulatory effects of acetyl-L-carnitine (ALCAR) on atherosclerosis in Wister rats and to explore its anti-atherosclerotic mechanism. MATERIAL AND METHODS We randomly divided 32 Wister rats into 4 groups: a normal diet group (control group, n=8), a normal diet+ALCAR group (ALCAR group, n=8), an atherosclerosis group (AS group, n=8), and an atherosclerosis+ALCAR group (AS+ALCAR group, n=8). The serum lipid distribution, oxidative stress, inflammatory factors and adiponectin (APN) in the blood, and heart and aortic tissues were determined using the standard assay kits, xanthine oxidase method, and ELISA, respectively. HE staining was performed to observe aortic pathology structure change, and the level of angiotensin II (AngII) in the aorta was assessed using radioimmunoassay. In addition, real-time quantitative PCR and Western blot analysis were applied to detect the expression of iNOS, IL-1ß, TNF-alpha, and CRP in the aortic and heart tissues. RESULTS Compared with the AS group, the levels of serum TC, TG, LDL, and VLDL in rats decreased significantly, while HDL level significantly increased in the AS+ALCAR group. ALCAR administration enhanced the SOD and GSH-Px activities and decreased MDA activity. APN level was significantly elevated in the AS group, but ALCAR had no significant effect on APN. Further, ALCAR reduced the expressions of inflammation factors TNF-alpha, IL-1ß, iNOS, and CRP, and the concentration of AngII in serum, aortic, and heart tissues. CONCLUSIONS ALCAR can inhibit the expressions of inflammatory factors and antioxidation to suppress the development of atherosclerosis by adjusting blood lipid in the myocardium of AS rats.

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 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.

Natural products - alpha-lipoic acid and acetyl-L-carnitine - in the treatment of chemotherapy-induced peripheral neuropathy.

OBJECTIVE: Cancer patients frequently experience Chemotherapy-Induced Peripheral Neuropathy (CIPN), as a typical side effect related to time of administration and dose of anticancer agents. Yet, CIPN pathophysiology is poorly understood, and there is a lack of well-tolerated pharmacological remedies helpful to prevent or treat it. Therefore, new safe and effective compounds are highly warranted, namely if based on an adequate understanding of the pathogenic mechanisms. MATERIAL AND METHODS: Herein we reviewed and discussed scientific data related to the beneficial role of some non-conventional treatments able to counteract CIPN, focusing our attention on alpha-lipoic acid (ALA) and L-acetyl-carnitine (LAC), two natural products that have been demonstrated to be promising preventive drugs. RESULTS: Although a growing body of in vitro and in vivo studies support ALA as a molecule able to counteract CIPN symptoms, mostly due to its antioxidant and anti-inflammatory properties, only two randomized clinical trials evaluated ALA usefulness in preventing chemotherapy-related neuropathy. Unfortunately, these studies were inconclusive and clinical outcomes showed to be highly dependent on the route of administration (oral versus or intravenous injection). LAC has demonstrated beneficial effects on both in vitro and in animal studies. Yet, some controversies aroused from randomized clinical trials. Indeed, while CIPN-patients treated with Taxane showed no benefit from LAC treatment, CIPN-patients treated with platinum compounds exhibit significant improvement of CIPN-related symptoms. Therefore, LAC treatment should be used, and thoroughly investigated only in patients treated with chemotherapy protocols Taxanes-free. CONCLUSIONS: Mechanisms of toxicity triggered by each single drug need to be deeply explored to better identify effective compounds to prevent or treat them. Moreover, additional experiments are mandatory to establish effective doses and length of treatment for each clinical situation in order to perform large and long-term randomized studies.

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.

Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.

Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in neurodegenerative diseases.

Acetyl-l-carnitine attenuates arsenic-induced liver injury by abrogation of mitochondrial dysfunction, inflammation, and apoptosis in rats.

Industrial and agricultural developments in recent years have resulted in the excessive discharge of arsenic into the environment, making arsenic toxicity a major worldwide concern. Oxidative stress is considered the primary mechanism for arsenic toxicity. The main objective of this study was to evaluate acetyl-l-carnitine's (ALC) protective ability against the arsenic-induced hepatotoxicity. For this purpose, male Wistar rats were distributed randomly into 5 groups of 8 rats each: control, arsenic (5 mg/kg) and arsenic plus ALC (5 mg/kg; 100, 200, 300 mg/kg). The animals were gavaged for 21 consecutive days. Liver tissue samples were extracted 24 h after the last treatment and were later analyzed for biochemical and histological alterations. The arsenic-induced oxidative damage was confirmed by elevation of malondialdehyde (MDA), a lipid peroxidation byproduct, as well as depletion in physiological antioxidant content such as superoxide dismutase (SOD) and catalase (CAT). Furthermore, alterations in mitochondrial functions including a significant decrease of mitochondrial outer membrane potential and reactive oxygen species (ROS) generation increase, mitochondrial swelling, release of cytochrome c and consequent activation of caspase-3 and caspase-9 and initiation of apoptosis, was observed following arsenic administration. Moreover, the inflammation was confirmed by the overexpression of inflammatory mediators such as NF-ĸB and IL-1 and IL-6. The present study demonstrated that ALC ameliorates arsenic-induced oxidative damage, mitochondrial dysfunction, apoptosis, inflammation and histological damage. ALC's protective features against arsenic hepatotoxicity may be due to this agent's antioxidant and anti-inflammatory properties as well as its stabilizing effects on mitochondrial function.

Modulatory effects of l-carnitine plus l-acetyl-carnitine on neuroendocrine control of hypothalamic functions in functional hypothalamic amenorrhea (FHA).

Functional hypothalamic amenorrhea (FHA) is a relatively frequent disease due to the combination of metabolic, physical, or psychological stressors. It is characterized by the low endogenous GnRH-induced gonadotropin secretion, thus triggering the ovarian blockade and a hypoestrogenic condition. Up to now various therapeutical strategies have been proposed, both using hormonal treatment as well as neuroactive compounds. Since carnitine, namely l-acetyl-carnitine (LAC), has been demonstrated to be effective in the modulation of the central hypothalamic control of GnRH secretion, we aimed to evaluate whether a combined integrative treatment for 12 weeks of LAC (250 mg/die) and l-carnitine (500 mg/die) was effective in improving the endocrine and metabolic pathways in a group of patients (n = 27) with FHA. After the treatment, interval mean LH plasma levels increased while those of cortisol and amylase decreased significantly. When patients were subdivided according to baseline LH levels, only hypo-LH patients showed the significant increase of LH plasma levels and the significant decrease of both cortisol and amylase plasma levels. The increased 17OHP/cortisol ratio, as index of the adrenal activity, demonstrated the reduced stress-induced adrenal activity. In conclusion, our data sustain the hypothesis that the integrative administration of LAC plus l-carnitine reduced both the metabolic and the neuroendocrine impairment of patients with FHA.

Possible effects of some agents on the injured nerve in obese rats: A stereological and electron microscopic study.

PURPOSE: The main aim of this study was to research new treatments following peripheral nerve injury involving melatonin (Mel), acetyl-l-carnitine (ALCAR), and leptin (Lep) using updated unbiased methods at the stereological and electron microscopic levels. MATERIALS AND METHODS: Wistar albino rats were randomly divided into nine equal groups; control (Cont), obese control (OG), obese group exposed to sciatic nerve resection (Gap) (OGG), obese group injected intraperitoneally (i.p.) with Mel (OMG), obese group injected with Mel i.p. with gap (OMGG), obese group injected with Lep i.p. (OLG), obese group injected with Lep i.p. with gap (OLGG), obese group injected with ALCAR i.p. (OAG), and obese group injected with ALCAR i.p. with gap (OAGG). Electromyography (EMG) procedures were performed. Following routine histological procedures, stereological analysis was performed for each group. RESULTS: In terms of the number of myelinated axons, high significant increase in OGG was observed compared to OG and Cont (p < 0.01). In addition, a highly significant increase in axon surface area and myelin thickness of OGG compared to OG and Cont (p < 0.01) was noted. A significant decrease in myelin thickness/axon diameter ratio of OGG was found in comparison with the other groups. In terms of latency, there was a highly significant decrease in OGG compared to Cont and OG (p < 0.01). Myelinated axon numbers in OAGG, OMGG and OLGG increased highly significantly compared to other groups (p < 0.01). Latency in OMGG, a highly significant increase, was determined in OMG compared to Cont (p < 0.01). In addition, latency values in OGG were highly significantly greater than in OAC and OAGG (p < 0.01). CONCLUSION: In particular, administration of Lep, Mel and ALCAR as neuroprotective agents may make a positive contribution to regeneration and myelination in obese rats.