BACKGROUND: Recent evidence indicates that insulin resistance in skeletal muscle may be related to reduce mitochondrial number and oxidation capacity. However, it is not known whether increasing mitochondrial number and function improves insulin resistance. In the present study, we investigated the effects of a combination of nutrients on insulin resistance and mitochondrial biogenesis/function in skeletal muscle of type 2 diabetic Goto-Kakizaki rats. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that defect of glucose and lipid metabolism is associated with low mitochondrial content and reduced mitochondrial enzyme activity in skeletal muscle of the diabetic Goto-Kakizaki rats. The treatment of combination of R-alpha-lipoic acid, acetyl-L-carnitine, nicotinamide, and biotin effectively improved glucose tolerance, decreased the basal insulin secretion and the level of circulating free fatty acid (FFA), and prevented the reduction of mitochondrial biogenesis in skeletal muscle. The nutrients treatment also significantly increased mRNA levels of genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-alpha (Ppar alpha), peroxisome proliferator-activated receptor-delta (Ppar delta), and carnitine palmitoyl transferase-1 (Mcpt-1) and activity of mitochondrial complex I and II in skeletal muscle. All of these effects of mitochondrial nutrients are comparable to that of the antidiabetic drug, pioglitazone. In addition, the treatment with nutrients, unlike pioglitazone, did not cause body weight gain. CONCLUSIONS/SIGNIFICANCE: These data suggest that a combination of mitochondrial targeting nutrients may improve skeletal mitochondrial dysfunction and exert hypoglycemic effects, without causing weight gain.

 After hind limb suspension, a remodeling of postural muscle phenotype is observed. This remodeling results in a shift of muscle profile from slow-oxidative to fast-glycolytic. These metabolic changes and fiber type shift increase muscle fatigability. Acetyl-L-carnitine (ALCAR) influences the skeletal muscle phenotype of soleus muscle suggesting a positive role of dietary supplementation of ALCAR during unloading. In the present study, we applied a 2-D DIGE, mass spectrometry and biochemical assays, to assess qualitative and quantitative differences in the proteome of rat slow-twitch soleus muscle subjected to disuse. Meanwhile, the effects of ALCAR administration on muscle proteomic profile in both unloading and normal-loading conditions were evaluated. The results indicate a modulation of troponin I and tropomyosin complex to regulate fiber type transition. Associated, or induced, metabolic changes with an increment of glycolytic enzymes and a decreased capacity of fat oxidation are observed. These metabolic changes appear to be counteracted by ALCAR treatment, which restores the mitochondrial mass and decreases the glycolytic enzyme expression, suggesting a normalization of the metabolic shift observed in unloaded animals. This normalization is accompanied by a maintenance of body weight and seems to prevent a switch of fiber type.

BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) disrupt neuronal mitochondrial DNA synthesis, resulting in antiretroviral toxic neuropathy (ATN). Acetyl-L-carnitine (ALCAR) enhances neurotrophic support of sensory neurones, potentially providing symptom relief and nerve regeneration. OBJECTIVE: The objective of the study was to assess the safety and efficacy compared to placebo of intramuscular ALCAR in HIV-positive patients with symptomatic distal symmetrical polyneuropathy. METHODS: Ninety patients were enrolled and randomized to receive ALCAR [500 mg twice a day (bid); n=43] or placebo (n=47) intramuscularly twice daily for 14 days followed by 42 days of oral ALCAR 1000 mg bid. Assessment of pain was obtained using the Visual Analogue Scale (VAS), Total Symptom Score (TSS), Clinical Global Impression of Change, McGill Pain Questionnaire (MPQ), and the need for rescue analgesics. RESULTS: There was no statistically significant difference in changes in VAS over 14 days between groups for the intent-to-treat (ITT) population, but for the efficacy-evaluable (EE) population ALCAR treatment produced a significantly greater reduction in pain compared with placebo (P=0.022). The proportion of patients with an improvement in TSS over 14 days was greater in the ALCAR group compared with the placebo group, but the differences were not statistically significant. During the open-label phase, patients experienced an improvement in pain, as measured by the VAS, TSS and McGill Pain Questionnaire. CONCLUSION: ALCAR, administered twice a day intramuscularly to HIV-1-infected patients with symptomatic ATN, significantly reduced weekly mean pain ratings on the VAS compared with placebo. Treatment with oral ALCAR improved symptoms for the patient group as a whole. Intramuscular and oral ALCAR was generally safe and well tolerated.

Attention deficit hyperactivity disorder (ADHD) is a frequent behavioral problem in young boys with fragile X syndrome (FXS), and its treatment is critical for improving social ability. The short-term efficacy of stimulant medications like methylphenidate (MPH) is well established in children with ADHD. FXS boys treated with MPH have improved attention span and socialization skills; however their mood becomes unstable at higher doses. Therefore, alternative pharmacological treatment of ADHD symptoms is desirable. A recent study showed that carnitine has a beneficial effect on the hyperactive-impulsive behavior in boys with ADHD without side effects. Our previous placebo-controlled trial indicated that L-acetylcarnitine (LAC) reduces hyperactivity in FXS boys. The objective of this study was to determine the efficacy of LAC in a larger sample of FXS boys with ADHD. The study design was randomized, double blind placebo controlled, parallel, and multicenter (with eight centers involved in Italy, France, and Spain). Sixty-three FXS males with ADHD (aged 6-13 years) were enrolled; 7 patients dropped out, 56 completed the one-year treatment, and 51 were included in the statistical analysis. Both groups improved their behavior, showing that psychosocial intervention has a significant therapeutic effect. However, we observed a stronger reduction of hyperactivity and improvement of social behavior in patients treated with LAC, compared with the placebo group, as determined by the Conners' Global Index Parents and the Vineland Adaptive Behavior Scale. Our results show that LAC (20-50 mg/kg/day) represents a safe alternative to the use of stimulant drugs for the treatment of ADHD in FXS children. Copyright 2008 Wiley-Liss, Inc.

A new technique for controllable elevation of night time growth hormone (GH) release in adult humans involves a synergy between oral intake of the naturally occurring compounds acetyl-L-carnitine (500 mg) and L-ornithine (25-100 mg) taken at night time sleep after a 3 to 4 hour fast. The set point for normal hypothalamic GH release appears to include a 'whole body' mitochondrial State 3 status 'feed back loop' controlled by systemic acetyl- L-carnitine levels. Copyright 2001 Harcourt Publishers Ltd.

AIMS AND BACKGROUND: In addition to bone marrow suppression and renal toxicity, neurotoxicity is a commonly occurring side effect of widely used chemotherapeutic agents like taxanes, cisplatin and vinca alkaloids. Neurotoxicity can cause antitumor therapy discontinuation or dose regimen modification. The aim of the present exploratory study was to investigate the activity of acetyl-L-carnitine in reversing peripheral neuropathy in patients with chemotherapy-induced peripheral neuropathy. METHODS AND STUDY DESIGN: Twenty-seven patients (16 males and 11 females) with paclitaxel and/or cisplatin-induced neuropathy (according to WHO recommendations for the grading of acute and subacute toxic effects) were enrolled. Patients received at least one cisplatin- (n = 5) or one paclitaxel- (n = 11) based regimen, or a combination of both (n = 11). Patients with chemotherapy-induced peripheral neuropathy were treated with acetyl-L-carnitine 1 g/die i.v. infusion over 1-2 h for at least 10 days. RESULTS: Twenty-six patients were evaluated for response having completed at least 10 days of acetyl-L-carnitine therapy (median, 14 days; range, 10-20). At least one WHO grade improvement in the peripheral neuropathy severity was shown in 73% of the patients. A case of insomnia related to ALC treatment was reported in one patient. Acetyl-L-carnitine seems to be an effective and well-tolerated agent for the treatment of chemotherapy-induced peripheral neuropathy. CONCLUSIONS: Our preliminary results should be confirmed in double-blind, placebo controlled studies.

OBJECTIVE: To determine the efficacy of combined l-carnitine and l-acetyl-carnitine therapy in infertile males with oligo-astheno-teratozoospermia. DESIGN: Placebo-controlled double-blind randomized trial. SETTING: University tertiary referral center. PATIENT(S): Sixty infertile patients (aged 20-40 years) with the following baseline sperm selection criteria: concentration, 10 to 40 x 10(6)/mL; forward motility,<15%; total motility, 10% to 40%; and atypical forms,<80%. Fifty-six patients completed the study. INTERVENTION(S): Patients were submitted to a combined treatment of l-carnitine (2 g/d) and l-acetyl-carnitine (1 g/d) or of placebo; the study design was 2 months' wash-out, 6 months of therapy or of placebo, and 2 months' follow-up. MAIN OUTCOME MEASURE(S): Variation in the semen parameters that were used for patient selection. RESULT(S): Even though increases were seen in all sperm parameters after combined carnitine treatment, the most significant improvement in sperm motility (both forward and total) was present in patients who had lower initial absolute values of motile sperm (<4 x 10(6) forward or<5 x 10(6) total motile spermatozoa per ejaculate). CONCLUSION(S): Combined treatment with l-carnitine and l-acetyl-carnitine in a controlled study of efficacy was effective in increasing sperm motility, especially in groups with lower baseline levels.

Efficacy, safety and tolerability of acetyl-L-carnitine (ALC) were studied during the double-blind placebo-controlled 12-week trial in patients with mild (initial) dementia caused by the Alzheimer's disease (AD) and vascular dementia (VD). ALC was administered in doses from 2250 to 3000 mg per day. Patient's state was assessed with some scales (MMSE, CGI etc) and a battery of neuropsychological tests. The treatment effect of ALC was 2,8 times higher than in placebo-treated patients. The clinical improvement by CGI scores was significantly better in AD patients compared to VD and did not depend on the severity of baseline cognitive deficit. The drug was well-tolerated. Carnicetine can be recommended in the abovementioned doses for treatment of early stages of AD and VD.

 Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN). In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment.

 Acetyl-L-carnitine (ALC) has gained clinical interest for its analgesic effect in different forms of neuropathies associated with chronic pain, such as diabetic and HIV-related peripheral neuropathies. The antinociceptive effect of ALC has been confirmed in several experimental models of neuropathic pain, including streptozotocin- and chemotherapy-induced neuropathy, and the sciatic nerve chronic constriction injury model. In these models, prophylactic administration of ALC has proven to be effective in preventing the development of neuropathic pain. In addition, ALC is known to produce a strong antinociceptive effect when given after neuropathic pain has been established. ALC can also improve the function of peripheral nerves by increasing nerve conduction velocity, reducing sensory neuronal loss, and promoting nerve regeneration. Analgesia requires repeated administrations of ALC, suggesting that the drug regulates neuroplasticity across the pain neuraxis. Recent evidence indicates that ALC regulates processes that go beyond its classical role in energy metabolism. These processes involve the activation of muscarinic cholinergic receptors in the forebrain, and an increased expression of type-2 metabotropic glutamate (mGlu2) receptors in dorsal root ganglia neurons. Induction of mGlu2 receptors is mediated by acetylation mechanisms that involve transcription factors of the nuclear factor (NF)-kappaB family.

Antiretroviral toxic neuropathy causes morbidity in human immunodeficiency virus (HIV) patients under dideoxynucleoside therapy, benefits only partially from medical therapy, and often leads to drug discontinuation. Proposed pathogeneses include a disorder of mitochondrial oxidative metabolism, eventually related to a reduction of mitochondrial DNA content, and interference with nerve growth factor activity. Carnitine is a substrate of energy production reactions in mitochondria and is involved in many anabolic reactions. Acetyl carnitine treatment promotes peripheral nerve regeneration and has neuroprotective properties and a direct analgesic role related to glutamatergic and cholinergic modulation. The aim of this study was to evaluate acetyl-l-carnitine in the treatment of painful antiretroviral toxic neuropathy in HIV patients. Twenty subjects affected by painful antiretroviral toxic neuropathy were treated with oral acetyl-l-carnitine at a dose of 2,000 mg/day for a 4-week period. Efficacy was evaluated by means of the modified Short Form McGill Pain Questionnaire with each item rated on an 11-point intensity scale at weekly intervals and by electromyography at baseline and final visit. Mean pain intensity score was significantly reduced during the study, changing from 7.35 +/- 1.98 (mean +/- SD) at baseline to 5.80 +/- 2.63 at week 4 (p = 0.0001). Electrophysiological parameters did not significantly change between baseline and week 4. In this study, acetyl-l-carnitine was effective and well tolerated in symptomatic treatment of painful neuropathy associated with antiretroviral toxicity. On the contrary, no effect was noted on neurophysiological parameters.

Peripheral nerve injury frequently results in functional morbidity since standard management fails to adequately address many of the neurobiological hurdles to optimal regeneration. Neuronal survival and regeneration are neurotrophin dependent and require increased aerobic capacity. Acetyl-l-carnitine (ALCAR) facilitates this need and prevents neuronal loss. ALCAR is clinically safe and is shown here to significantly improve nerve regeneration and target organ reinnervation. Two groups of five rats underwent sciatic nerve division followed by immediate repair. One group received parenteral ALCAR (50mg/kg/day) from time of operation until termination at 12 weeks. A 'sham treatment' group received normal saline. A third group was left unoperated and did not receive any treatment. A segment of nerve was harvested between 5mm proximal and 10mm distal to the repair in operated groups, and at the corresponding level in the unoperated group. Mean axonal count in normal, non-axotomised nerve was 14,720 (SD 2378). That of the saline group (17,217 SD 1808) was not significantly different from normal nerve (P=0.0985). Mean number of myelinated axons in the ALCAR group (24,460 SD 3750) was significantly greater than both sham group (P<0.01) and normal nerve (P=0.0012). Mean myelin thickness in the saline treated group (0.408 microm SD 0.067 microm) was less than normal nerve (0.770 microm SD 0.143 microm) (P<0.001). Mean myelin thickness in the ALCAR group (0.627 microm SD 0.052 microm) was greater than the sham (saline) group (P<0.01) and not statistically different from normal nerve (P=0.07). ALCAR increased dermal PGP9.5 staining by 210% compared to sham treatment (P<0.0001) and significantly reduced the mean percentage weight loss in gastrocnemius muscle (ALCAR group 0.203% vs. 0.312% in sham group P=0.015). ALCAR not only increases the number of regenerating nerve fibres but also morphologically improves the quality of regeneration and target organ reinnervation. Adjuvant ALCAR treatment may improve both sensory and motor outcomes and merits further investigation.

The analgesic activity of acetyl-L-carnitine (ALCAR) in neuropathic pain is well established. By contrast, its potential efficacy in the relief of acute pain has not been reported. The antinociceptive effect of ALCAR was, therefore, examined in the mouse hot-plate and abdominal constriction tests, and in the rat paw-pressure test. ALCAR (100 mg kg(-1) s.c. twice daily for seven days) produced an increase of the pain threshold in both mice and rats. ALCAR was also able to reverse hyperalgesia induced by kainic acid and NMDA administration in the mouse hot-plate test. The antinociception produced by ALCAR was prevented by the unselective muscarinic antagonist atropine, the M(1) selective antagonists pirenzepine and S-(-)-ET126, and by the choline uptake inhibitor hemicholinium-3 (HC-3). By contrast the analgesic effect of ALCAR was not prevented by the opioid antagonist naloxone, the GABA(B) antagonist CGP 35348, the monoamine synthesis inhibitor (alpha)-methyl-p-tyrosine, and the Gi-protein inactivator pertussis toxin. Moreover, ALCAR antinociception was abolished by pretreament with an antisense oligonucleotide (aODN) against the M(1) receptor subtype, administered at the dose of 2 nmol per single i.c.v injection. On the basis of the above data, it can be postulated that ALCAR exerted an antinociceptive effect mediated by a central indirect cholinergic mechanism. In the antinociceptive dose-range, ALCAR did not impair mouse performance evaluated by the rota-rod and hole-board tests.

This study examines the potential efficacy of acetyl-L-carnitine (ALC) to prevent and treat paclitaxel-induced pain. Rats received four intraperitoneal (i.p.) injections of 2 mg/kg paclitaxel on alternate days which, following a short delay induced marked mechanical hypersensitivity. Daily administration of ALC (50 mg/kg and 100 mg/kg; p.o.; concurrently with paclitaxel and for 14 days afterwards) prevented the development of paclitaxel-induced pain. This effect was long lasting, for at least 3 weeks after the last dose of ALC. In a separate experiment, daily administration of ALC (100 mg/kg; p.o.; for 10 days) to rats with established paclitaxel-induced pain produced an analgesic effect. This effect dissipated shortly after ALC treatment was withdrawn. We conclude that ALC may be useful in the prevention and treatment of chemotherapy-induced painful peripheral neuropathy.

 Variations in energy balance, body composition, and nutrient partitioning induced by acetyl-L-carnitine (ALCAR) supplementation were studied in young (2 mo) and old (24 mo) Wistar rats. Changes in skeletal muscle metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were administered 0 (control) or 15 g/L ALCAR in their drinking water for 1 mo. ALCAR treatment significantly decreased body lipid percentage in young rats and significantly increased body protein percentage in old rats. The percentage of metabolizable energy (ME) intake stored as lipid was lower in ALCAR-treated young rats, whereas the percentage of ME intake stored as protein was greater in ALCAR-treated old rats compared with their age-matched controls. In addition, ALCAR supplementation significantly decreased serum leptin levels in old rats. Elevated skeletal muscle respiration was found in old rats treated with ALCAR, due to an increase in mitochondrial protein mass. In conclusion, ALCAR supplementation decreases efficiency of lipid deposition in young rats and increases efficiency of protein deposition in old rats. In addition, ALCAR supplementation partly reduces the leptin resistance that occurs in old rats, and improves ATP production in skeletal muscle mitochondria through an increase in mitochondrial protein content.

BACKGROUND: Nucleoside analogue reverse transcriptase inhibitors (NRTI) disrupt neuronal mitochondrial DNA synthesis, impairing energy metabolism and resulting in a distal symmetrical polyneuropathy (DSP), an antiretroviral toxic neuropathy (ATN) that causes significant morbidity in HIV disease. Serum acetyl-l-carnitine (ALCAR) levels are decreased in neuropathy associated with NRTI therapy. ALCAR enhances neurotrophic support of sensory neurons and promotes energy metabolism, potentially causing nerve regeneration and symptom relief. OBJECTIVE: To assess the efficacy of oral ALCAR (1500 mg twice daily) for up to 33 months in an open cohort of 21 HIV-positive patients with established ATN. METHODS: Skin biopsies were excised from the leg before ALCAR treatment, at 6-12 month intervals thereafter and from HIV-negative non-neuropathic controls. Fibre types in epidermal, dermal and sweat gland innervation were quantified immunohistochemically. RESULTS: After 6 month's treatment, mean immunostaining area for small sensory fibres increased (epidermis 100%, P = 0.006; dermis 133%, P<0.05) by more than that for all fibre types (epidermis 16%, P = 0.04; dermis 49%, P<0.05; sweat glands 60%, P<0.001) or for sympathetic fibres (sweat glands 41%, P<0.0003). Compared with controls, epidermal, dermal and sweat gland innervation reached 92%, 80% and 69%, respectively, after 6 month's treatment. Innervation improvements continued (epidermis and dermis) or stabilized (sweat glands) after 24 month's treatment. Neuropathic grade improved in 76% of patients and remained unchanged in 19%. HIV RNA load, CD4 and CD8 cell counts did not alter significantly throughout the study. CONCLUSIONS: ALCAR treatment improves symptoms, causes peripheral nerve regeneration and is proposed as a pathogenesis-based treatment for DSP.

Oxidative stress and secondary excitotoxicity, due to cellular energy deficit, are major factors playing roles in 3-nitropropionic acid (3-NPA) induced mitochondrial dysfunction. Acute or chronic exposure to 3-NPA also leads to neuronal degeneration in different brain regions. The present study quantitatively assessed peripheral neuropathy induced by chronic exposure to 3-NPA in rats. The neuroprotective abilities of two antioxidants, acetyl-l-carnitine and resveratrol, were investigated as well. Rats were exposed for up to four weeks to 3-NPA alone or 3-NPA combined with acetyl-l-carnitine or resveratrol, administered peripherally. The experimental outcome was evaluated by neurophysiological, histological, and morphometric analyses. Rats exposed to 3-NPA developed hind limb paresis. Furthermore, a significant decrease in motor nerve conduction velocity (MCV) was detected in tail nerves and axonal degeneration in sciatic nerves (p<0.05). Treatment with resveratrol prevented the functional effects of 3-NPA exposure, whereas treatment with acetyl-l-carnitine, preventing paresis, was not effective to MCV and morphological changes. These data suggest that resveratrol is a good candidate for treatment of metabolic neuropathy. The experimental outcome of this study shows that chronic treatment with 3-NPA in rats is relevant in development of an experimental model of toxic neuropathy.