Oxidative stress in the cardiovascular system, including brain microvessels and/or parenchymal cells results in an accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) compounds thus promoting leukocyte adhesion and increasing endothelial permeability. The resulting chronic injury stimulus results in progressive cellular hypometabolism. We propose that hypometabolism, coupled with oxidative stressors, is responsible for most Alzheimer disease (AD) and cerebrovascular accidents (CVAs) and appears to be a central initiating factor for vascular abnormalities, mitochondrial damage and an imbalance in the activity of vasoactive substances, such as different isoforms of nitric oxide synthase (NOS), endothelin-1 (ET-1), oxidative stress markers, mtDNA and mitochondrial enzymes in the vascular wall and in brain parenchymal cells. At higher concentrations, ROS induces cell injury and death, which occurs during the aging process, where accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms, especially in the mitochondria. Vascular endothelial and neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, which can cause a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondrial DNA abnormalities such as overproliferation and or deletion can be used as a key marker for diseases differentiation and effectiveness of the treatment. We speculate that specific antioxidants such as acetyl-L-carnitine and R-alpha lipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and restore the normal cellular function, making these antioxidants very powerful alternate strategies for the treatment of cardiovascular cerebrovascular as well as neurodegenerative diseases including AD. Future potential exploration using mtDNA markers can be considered more accurate hallmarks for diagnosis and monitoring treatment of human diseases. The present article discusses some of the patents regarding the oxidative stress.

OBJECTIVE

Cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine plays an essential role in mitochondrial metabolism and in modulating excess acyl-coenzyme A (acyl-CoA) levels. The effects of cerebral ischemia on carnitine metabolism are not well understood, although the newborn may be particularly vulnerable to carnitine deficiency. We used a newborn rat model of hypoxia-ischemia (HI) to test the hypothesis that HI alters acyl-CoA:CoA homeostasis and that this effect can be prevented by treatment with carnitine.

METHODS

A total of 120 postnatal day 7 rats were subjected to 70 minutes of HI after treatment with 16 mmol/kg intraperitoneal l-carnitine or diluent. Carnitine, acylcarnitines, and excitatory amino acids were measured by mass spectrometry, and carnitine acetyl transferase activity, superoxide, and levels of the mitochondrial phospholipid cardiolipin (CL) were measured at 2- and 24-hour recovery.

RESULTS

HI and hypoxia were associated with a significant increase in the ratio of acyl-CoA:CoA, which was prevented by treatment with carnitine. Carnitine treatment also prevented increases in glutamate, glycine, superoxide, and decrease of CL.

CONCLUSIONS

Carnitine metabolic pathways are compromised in HI and hypoxia. The protective effect of carnitine treatment on HI injury may be attributable to maintaining mitochondrial function.

Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases and by a panel of experts that treat ASD individuals. Only a few anti-epileptic drugs (AEDs) have undergone carefully controlled trials in ASD, but these trials examined outcomes other than seizures. Several lines of evidence point to valproate, lamotrigine, and levetiracetam as the most effective and tolerable AEDs for individuals with ASD. Limited evidence supports the use of traditional non-AED treatments, such as the ketogenic and modified Atkins diet, multiple subpial transections, immunomodulation, and neurofeedback treatments. Although specific treatments may be more appropriate for specific genetic and metabolic syndromes associated with ASD and seizures, there are few studies which have documented the effectiveness of treatments for seizures for specific syndromes. Limited evidence supports l-carnitine, multivitamins, and N-acetyl-l-cysteine in mitochondrial disease and dysfunction, folinic acid in cerebral folate abnormalities and early treatment with vigabatrin in tuberous sclerosis complex. Finally, there is limited evidence for a number of novel treatments, particularly magnesium with pyridoxine, omega-3 fatty acids, the gluten-free casein-free diet, and low-frequency repetitive transcranial magnetic simulation. Zinc and l-carnosine are potential novel treatments supported by basic research but not clinical studies. This review demonstrates the wide variety of treatments used to treat seizures in individuals with ASD as well as the striking lack of clinical trials performed to support the use of these treatments. Additional studies concerning these treatments for controlling seizures in individuals with ASD are warranted.

The topic of exercise-induced skeletal muscle injury has received considerable attention in recent years. Likewise, strategies to minimise the injury resulting from heavy resistance exercise have been studied. Over the past 15 years, several investigations have been performed focused on the role of nutritional supplements to attenuate signs and symptoms of muscle injury. Of these, some have reported favourable results, while many others have reported no benefit of the selected nutrient. Despite these mixed findings, recommendations for the use of nutritional supplements for the purposes of attenuating muscle injury are rampant within the popular fitness media and athletic world, largely without scientific support. Those nutrients include the antioxidant vitamin C (ascorbic acid) and vitamin E (tocopherol), N-acetyl-cysteine, flavonoids, L-carnitine, astaxanthin, beta-hydroxy-beta-methylbutyrate, creatine monohydrate, essential fatty acids, branched-chain amino acids, bromelain, proteins and carbohydrates. A discussion of all published peer-reviewed articles in reference to these nutrients and their impact on resistance exercise-induced skeletal muscle injury is presented, in addition to a brief view into the potential mechanism of action for each nutrient.Based on the current state of knowledge, the following conclusions can be made with regard to nutritional supplements and their role in attenuating signs and symptoms of skeletal muscle injury occurring as a consequence of heavy resistance exercise: (i) there appears to be a potential role for certain supplements (vitamin C, vitamin E, flavonoids, and L-carnitine); (ii) these supplements cannot effectively eliminate muscle injury, only attenuate certain signs and symptoms; (iii) it is presently unclear what the optimal dosage of these nutrients is (whether used alone or in combination); (iv) it is unclear what the optimal pretreatment period is; and (v) the effectiveness is largely specific to non-resistance trained individuals.Ultimately, because so few studies have been conducted in this area, it is difficult to recommend with confidence the use of selected nutrients for the sole purpose of minimising signs and symptoms of resistance exercise-induced muscle injury, in particular with regard to resistance-trained individuals.

The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.

OBJECTIVE

To test the hypothesis that acetyl-L-carnitine (ALCAR) promotes neurologic recovery from experimental focal cerebral ischemia (stroke) in rats.

METHODS

We conducted a prospective, randomized, blinded study in which adult male Sprague-Dawley rats were subjected to coagulative occlusion of the distal right middle cerebral artery (MCA) and temporary occlusion of both common carotid arteries (CCAs) for 60 minutes. After the onset of ischemia each rat was given ALCAR (200 mg/kg) or a similar volume of drug vehicle. Neurologic evaluation was performed on postoperative days 1, 2, 3, and 7. Postoperative weight loss was measured at day 7. Infarct volume was measured in separate groups of rats at 24 hours.

RESULTS

Neurologic outcomes, as assessed with an 11-point neurologic deficit scoring system, were significantly improved in ALCAR-treated rats on days 1, 2, and 3 (P < .05). Improvement approached significance on day 7. Rats treated with ALCAR also demonstrated significantly less weight loss on day 7 compared with the vehicle-treated controls. We detected no differences, however, in infarct volumes measured between treatment groups.

CONCLUSIONS

Although we noted no differences in infarct volume, postischemic treatment with ALCAR did improve early clinical recovery and prevented significant weight loss in this rat model of focal cerebral ischemia.

The abnormalities underlying diabetic neuropathy appear to be multiple and involve metabolic neuronal and vasomediated defects. The accumulation of long-chain fatty acids and impaired beta-oxidation due to deficiencies in carnitine and/or its esterified derivatives, such as acetyl-L-carnitine, may have deleterious effects. In the present study, we examined, in the diabetic bio-breeding Worcester rat, the short- and long-term effects of acetyl-L-carnitine administration on peripheral nerve polyols, myoinositol, Na+/K+ -ATPase, vasoactive prostaglandins, nerve conduction velocity, and pathologic changes. Short-term prevention (4 mo) with acetyl-L-carnitine had no effects on nerve polyols, but corrected the Na+/K+ -ATPase defect and was associated with 63% prevention of the nerve conduction defect and complete prevention of structural changes. Long-term prevention (8 mo) and intervention (from 4 to 8 mo) with acetyl-L-carnitine treatment normalized nerve PGE(1) whereas 6-keto PGF(1-alpha) and PGE(2) were unaffected. In the prevention study, the conduction defect was 73% prevented and structural abnormalities attenuated. Intervention with acetyl-L-carnitine resulted in 76% recovery of the conduction defect and corrected neuropathologic changes characteristic of 4-mo diabetic rats. Acetyl-L-carnitine treatment promoted nerve fiber regeneration, which was increased two-fold compared to nontreated diabetic rats. These results demonstrate that acetyl-L-carnitine has a preventive effect on the acute Na+/- K+_ATPase defect and a preventive and corrective effect on PGE1 in chronically diabetic nerve associated with improvements of nerve conduction velocity and pathologic changes.

Acetyl-L-carnitine (ALC) has been shown to facilitate the repair of transected sciatic nerves. The effect of ALC (50 mg/kg/d) on the diminished nerve conduction velocity (NCV) of rats with streptozotocin (STZ)-induced hyperglycemia of 3 weeks' duration was evaluated. The aldose reductase inhibitor, sorbinil, which is reported to normalize the impaired NCV associated with experimental diabetes, was used as a positive control. Aldose reductase inhibitors are thought to have an effect by decreasing peripheral nerve sorbitol content and increasing nerve myo-inositol. Treatment of STZ-diabetic rats with either ALC or sorbinil resulted in normal NCV. Sorbinil treatment was associated with normalized sciatic nerve sorbitol and myo-inositol; ALC treatment did not reduce the elevated sorbitol levels, but sciatic nerve myo-inositol content was no different from nondiabetic levels. Both ALC and sorbinil treatment of STZ-diabetic rats were associated with a reduction in the elevated malondialdehyde (MDA) content of diabetic sciatic nerve, indicating reduced lipid peroxidation. The beneficial effects of sorbinil and ALC on the altered peripheral nerve function associated with diabetes were similar, but their effects on the polyol pathway (frequently implicated in the pathogenesis of peripheral neuropathy) were different.

The purpose of this study was to reveal synaptic plasticity within the dorsal cochlear nucleus (DCN) as a result of noise trauma and to determine whether effective antioxidant protection to the cochlea can also impact plasticity changes in the DCN. Expression of synapse activity markers (synaptophysin and precerebellin) and ultrastructure of synapses were examined in the DCN of chinchilla 10 days after a 105 dB SPL octave-band noise (centered at 4 kHz, 6 h) exposure. One group of chinchilla was treated with a combination of antioxidants (4-hydroxy phenyl N-tert-butylnitrone, N-acetyl-l-cysteine and acetyl-l-carnitine) beginning 4 h after noise exposure. Down-regulated synaptophysin and precerebellin expression, as well as selective degeneration of nerve terminals surrounding cartwheel cells and their primary dendrites were found in the fusiform soma layer in the middle region of the DCN of the noise exposure group. Antioxidant treatment significantly reduced synaptic plasticity changes surrounding cartwheel cells. Results of this study provide further evidence of acoustic trauma-induced neural plasticity in the DCN and suggest that loss of input to cartwheel cells may be an important factor contributing to the emergence of hyperactivity in the DCN after noise exposure. Results further suggest that early antioxidant treatment for acoustic trauma not only rescues cochlear hair cells, but also has impact on central auditory structures.

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.

Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions.

Several hundred thousand peripheral nerve injuries occur each year in Europe alone. Largely due to the death of around 40% of primary sensory neurons, sensory outcome remains disappointingly poor despite considerable advances in surgical technique; yet no clinical therapies currently exist to prevent this neuronal death. Acetyl- L-carnitine (ALCAR) is a physiological peptide with roles in mitochondrial bioenergetic function, which may also increase binding of nerve growth factor by sensory neurons. Following unilateral sciatic nerve transection, adult rats received either one of two doses of ALCAR or sham, or no treatment. Either 2 weeks or 2 months later, LLL [TdT (terminal deoxyribonucleotidyl transferase) uptake nick end labelling] and neuron counts obtained using the optical disector technique. Sham treatment had no effect upon neuronal death. ALCAR treatment caused a large reduction in the number of TUNEL-positive neurons 2 weeks after axotomy (sham treatment 33/group; low-dose ALCAR 6/group, P=0.132; high-dose ALCAR 3/group, P<0.05), and almost eliminated neuron loss (sham treatment 21%; low-dose ALCAR 0%, P=0.007; high-dose ALCAR 2%, P<0.013). Two months after axotomy the neuroprotective effect of high-dose ALCAR treatment was preserved for both TUNEL counts (no treatment five/group; high-dose ALCAR one/group) and neuron loss (no treatment 35%; high-dose ALCAR -4%, P<0.001). These results provide further evidence for the role of mitochondrial bioenergetic dysfunction in post-traumatic sensory neuronal death, and also suggest that acetyl- L-carnitine may be the first agent suitable for clinical use in the prevention of neuronal death after peripheral nerve trauma.

The degradation of medium-chained dicarboxylic (DC) acids was investigated on purified mitochondria and peroxisomes. Intact organelles were incubated with dodecanedioic acid (DC12), suberic acid (DC8) and adipic acid (DC6), and the production of lower-chained DC-acids and of acetyl-CoA + acetyl-carnitine was monitored. It was shown, that intact peroxisomes could beta-oxidize DC12, DC10, and DC8 at least as far as DC6, while intact mitochondria readily beta-oxidized DC12, and DC10 as far as succinic acid. DC8 and DC6 were not oxidized by intact mitochondria when these two acids were presented externally to the intact organelle. When they were formed intramitochondrially from DC12 and DC10, both DC8 and DC6 were, however, to a great extent beta-oxidized as far as succinic acid. The major reason for this difference between mitochondrial oxidation of externally and internally located DC8 and DC6 seems to be an inability to transport these two acids through the mitochondrial membrane. For DC12 and DC10, the mitochondrial transport systems, which were indicated to be identical to the systems used by the corresponding monocarboxylic acids, were found to be rate-limiting in the beta-oxidation of these acids. A contributing factor to the undetectable beta-oxidation of externally located DC8 and DC6 may also be, that the Km values of DC8-CoA (460 +/- 70 mumol/l) and DC6-CoA (980 +/- 90 mumol/l) towards the acyl-CoA dehydrogenases are very high. These results imply that very high concentrations of intermediates are created intramitochondrially during beta-oxidation, concentrations which are probably only formed through formation of DC8-CoA and DC6-CoA from longer DC-acids and not by transport from outside the mitochondria. The data presented thus for the first time give evidence to a pathway for medium-chained monocarboxylic acids (especially lauric acid and decanoic acid) through cytosolic omega-oxidation followed by activation, transport over the mitochondrial membrane and beta-oxidation to succinic acid.

OBJECTIVE

Evidence shows that alcohol intake causes oxidative neuronal injury and neurocognitive deficits that are distinct from the classical Wernicke-Korsakoff neuropathy. Our previous findings indicated that alcohol-elicited blood-brain barrier (BBB) damage leads to neuroinflammation and neuronal loss. The dynamic function of the BBB requires a constant supply and utilization of glucose. Here we examined whether interference of glucose uptake and transport at the endothelium by alcohol leads to BBB dysfunction and neuronal degeneration.

METHODS

We tested the hypothesis in cell culture of human brain endothelial cells, neurons and alcohol intake in animal by immunofluorescence, Western blotting and glucose uptake assay methods.

RESULTS

We found that decrease in glucose uptake correlates the reduction of glucose transporter protein 1 (GLUT1) in cell culture after 50 mM ethanol exposure. Decrease in GLUT1 protein levels was regulated at the translation process. In animal, chronic alcohol intake suppresses the transport of glucose into the frontal and occipital regions of the brain. This finding is validated by a marked decrease in GLUT1 protein expression in brain microvessel (the BBB). In parallel, alcohol intake impairs the BBB tight junction proteins occludin, zonula occludens-1, and claudin-5 in the brain microvessel. Permeability of sodium fluorescein and Evans Blue confirms the leakiness of the BBB. Further, depletion of trans-endothelial electrical resistance of the cell monolayer supports the disruption of BBB integrity. Administration of acetyl-L: -carnitine (a neuroprotective agent) significantly prevents the adverse effects of alcohol on glucose uptake, BBB damage and neuronal degeneration.

CONCLUSIONS

These findings suggest that alcohol-elicited inhibition of glucose transport at the blood-brain interface leads to BBB malfunction and neurological complications.

Several studies have suggested that antioxidants retard the process of cataractogenesis by scavenging free oxygen radicals. The present study sought to assess the efficacy of the antioxidant acetyl-L-carnitine (ALCAR) in preventing selenite-induced cataractogenesis in an experimental setting. The first, in vitro phase of the study was performed on lenses from Wistar rats incubated for 24 h at 37 degrees C in Dulbecco's Modified Eagle Medium (DMEM) alone (control, Group I), or in DMEM containing 100 microM of selenite (Group II) or in DMEM containing 100 microM of selenite and 200 microM/ml ALCAR added at the same time as selenite (Group IIIa) or 30 min, 1 h or 2 h later (Groups IIIb, IIIc and IIId, respectively). Gross morphological examination of these lenses revealed dense opacification (cataract formation) in Group II, minimal opacification in some Group IIIa lenses and no opacification in Group I. The mean activities of the antioxidant enzymes catalase and glutathione peroxidase were significantly lower in Group II than in Group I or Group IIIa lenses, while malondialdehyde concentration (an indicator of lipid peroxidation) was significantly higher in Group II lenses than that in Group I or Group IIIa lenses. The second, in vivo phase of the study revealed dense opacification (cataract formation) in 100% of Wistar rat pups receiving subcutaneous sodium selenite alone (19 microM/kg body weight) but in only 37.5% of those receiving subcutaneous selenite and intraperitoneal ALCAR. These data suggest that ALCAR is able to significantly retard experimental selenite-induced cataractogenesis.

OBJECTIVE

We compared the effects of acetylcarnitine, propionylcarnitine and both compounds on the symptoms of chronic fatigue syndrome (CFS).

METHODS

In an open, randomized fashion we compared 2 g/d acetyl-L-carnitine, 2 g/d propionyl-L-carnitine, and its combination in 3 groups of 30 CFS patients during 24 weeks. Effects were rated by clinical global impression of change. Secondary endpoints were the Multidimensional Fatigue Inventory, McGill Pain Questionnaire, and the Stroop attention concentration test. Scores were assessed 8 weeks before treatment; at randomization; after 8, 16, and 24 weeks of treatment; and 2 weeks later.

RESULTS

Clinical global impression of change after treatment showed considerable improvement in 59% of the patients in the acetylcarnitine group and 63% in the propionylcarnitine group, but less in the acetylcarnitine plus propionylcarnitine group (37%). Acetylcarnitine significantly improved mental fatigue (p =.015) and propionylcarnitine improved general fatigue (p =.004). Attention concentration improved in all groups, whereas pain complaints did not decrease in any group. Two weeks after treatment, worsening of fatigue was experienced by 52%, 50%, and 37% in the acetylcarnitine, propionylcarnitine, and combined group, respectively. In the acetylcarnitine group, but not in the other groups, the changes in plasma carnitine levels correlated with clinical improvement.

CONCLUSIONS

Acetylcarnitine and propionylcarnitine showed beneficial effect on fatigue and attention concentration. Less improvement was found by the combined treatment. Acetylcarnitine had main effect on mental fatigue and propionylcarnitine on general fatigue.

Sparse-fur (spf) mice with a deficiency of hepatic ornithine transcarbamylase (OTC) are congenitally hyperammonemic, showing elevated cerebral ammonia and glutamine and depleted levels of energy metabolites. This mouse disorder is akin to the human OTC deficiency, in which neuronal loss and Alzheimer's type II astrocytosis is reported. Reduced cytochrome C oxidase (COX) activity is characteristic of neurodegeneration in Alzheimer's type disorders. We have studied the causal relationship between cerebral COX activity and energy depletion in spf mice. Our results indicate a progressive decrease in the COX activity in various brain regions in spf mice, up to 40 weeks of age, which severely effected the cerebral levels of various energy metabolites. A quantitative estimation of cerebral COX subunit I mRNA also showed a tendency to decrease in spf mice. Short-term acetyl L-carnitine (ALCAR) treatment restored these abnormalities. Our study points out that: (a) ammonia-induced alterations in the cerebral reducing equivalents could cause a decrease in COX activity and its mRNA expression, and (b) ALCAR administration could normalize the cerebral energy metabolism and induce COX mRNA expression and activity.

Oxidative damage of the endothelium disrupts the integrity of the blood-brain barrier (BBB). We have shown before that alcohol exposure increases the levels of reactive oxygen species (ROS; superoxide and hydroxyl radical) and nitric oxide (NO) in brain endothelial cells by activating NADPH oxidase and inducible nitric oxide synthase. We hypothesize that impairment of antioxidant systems, such as a reduction in catalase and superoxide dismutase (SOD) activity, by ethanol exposure may elevate the levels of ROS/NO in endothelium, resulting in BBB damage. This study examines whether stabilization of antioxidant enzyme activity results in suppression of ROS levels by anti-inflammatory agents. To address this idea, we determined the effects of ethanol on the kinetic profile of SOD and catalase activity and ROS/NO generation in primary human brain endothelial cells (hBECs). We observed an enhanced production of ROS and NO levels due to the metabolism of ethanol in hBECs. Similar increases were found after exposure of hBECs to acetaldehyde, the major metabolite of ethanol. Ethanol simultaneously augmented ROS generation and the activity of antioxidative enzymes. SOD activity was increased for a much longer period of time than catalase activity. A decline in SOD activity and protein levels preceded elevation of oxidant levels. SOD stabilization by the antioxidant and mitochondria-protecting agent acetyl-L-carnitine (ALC) and the anti-inflammatory agent rosiglitazone suppressed ROS levels, with a marginal increase in NO levels. Mitochondrial membrane protein damage and decreased membrane potential after ethanol exposure indicated mitochondrial injury. These changes were prevented by ALC. Our findings suggest the counteracting mechanisms of oxidants and antioxidants during alcohol-induced oxidative stress at the BBB. The presence of enzymatic stabilizers favors the ROS-neutralizing antioxidant redox of the BBB, suggesting an underlying protective mechanism of NO for brain vascular tone and vasodilation.

OBJECTIVE

To examine the role of acetyl-L-carnitine (ALC) in the treatment of diabetic peripheral neuropathy (DPN).

METHODS

A MEDLINE search (1966-April 2008) of the English-language literature was performed using the search terms carnitine, diabetes, nerve, and neuropathy. Studies identified were then cross-referenced for their citations.

METHODS

The search was limited to clinical trials, meta-analyses, and reviews addressing the use of ALC for the treatment of DPN. Studies that included other disease states that could cause peripheral neuropathy were excluded. Two large clinical studies that used ALC for the treatment of DPN were identified. No case studies were identified.

RESULTS

The results from 2 published clinical trials involving 1679 subjects were included. Subjects who received at least 2 g daily of ALC showed decreases in pain scores. One study showed improvements in electrophysiologic factors such as nerve conduction velocities, while the other did not. Patients who had neuropathic pain reported reductions in pain using a visual analog scale. Nerve regeneration was documented in one trial. The supplement was well tolerated. A proprietary form of ALC was used in both studies.

CONCLUSIONS

Data on treatment of DPN with ALC support its use. It should be recommended to patients early in the disease process to provide maximal benefit. Further studies should be conducted to determine the effectiveness of ALC in the treatment and prevention of the worsening symptoms of DPN.

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.

The effect of acetyl-L-carnitine (ALC) on the spontaneous release of acetylcholine (ACh) in the striatum and hippocampus of freely moving rats was investigated using brain microdialysis coupled with HPLC-electrochemical detection. Systemic administration of ALC, in a dose-dependent manner, stimulated ACh release in both areas, while the D-enantiomer was substantially ineffective. The effect of ALC was strongly Ca2+ dependent and tetrodotoxin (TTX) sensitive. These features of an exocytotic and impulse flow-dependent mechanism suggest that the increase in ACh release is the result of ALC activation of a physiological mechanism in cholinergic neurons.

Sparse-fur (spf) mouse is the ideal animal model to study the neuropathology of congenital ornithine transcarbamylase (OTC) deficiency. Our current hypothesis implies that an ammonia-induced depletion of energy metabolism in the spf mouse, could be due to a reduction in the activities of the enzymes of the electron transport chain and a treatment with acetyl-L-carnitine could normalize this abnormality. We also hypothesized that there might be a differential degree of inhibition in synaptosomal and non-synaptic mitochondria, for the enzymes of the electron transport chain, caused by congenital hyperammonemia. We have therefore measured the activities of NADH-cytochrome C oxidoreductase, succinate cytochrome C oxidoreductase and cytochrome C oxidase in synaptosomes and non-synaptic mitochondria, isolated from spf mice and CD-1 controls with and without acetyl-L-carnitine treatment. Our results indicate a significant reduction (19-34%) in the activities of these complexes in synaptosomes in untreated spf mice, whereas in non-synaptic mitochondria, there was a tendency for the activities to decrease. Acetyl-L-carnitine treatment enhanced these activities (15-64%) for all the three enzyme complexes and its effect was more prominent on succinate cytochrome C oxidoreductase activity (64%). These studies point out that: (a) ammonia-induced disturbances in the energy metabolism could be more pronounced in neuronal mitochondria, and (b) the effect of acetyl-L-carnitine on the restoration of cerebral ATP in hyperammonemia could be through an enhancement of the activities of various electron transport chain enzymes.

Following distal nerve injury significant sensory neuronal cell death occurs in the dorsal root ganglia, while after a more proximal injury, such as brachial plexus injury, a sizeable proportion of spinal motoneurons also undergo cell death. This phenomenon has been undervalued for a long time, but it has a significant role in the lack of functional recuperation, as neuronal cells cannot divide and be replaced, hence the resulting nerve regeneration is usually suboptimal. It is now accepted that this cell death is due to apoptosis, as indicated by analysis of specific genes involved in the apoptotic signalling cascade. Immediate nerve repair, either by direct suturing or nerve grafting, gives a degree of neuroprotection, but this approach does not fully prevent neuronal cell death and importantly it is not always possible. Our work has shown that pharmacological intervention using either acetyl-L-carnitine (ALCAR) or N-acetyl-cysteine (NAC) give complete neuroprotection in different types of peripheral nerve injury. Both compounds are clinically safe and experimental work has defined the best dose, timing after injury and duration of administration. The efficacy of neuroprotection of ALCAR and NAC can be monitored non-invasively using MRI, as demonstrated experimentally and more recently by clinical studies of the volume of dorsal root ganglia. Translation to patients of this pharmacological intervention requires further work, but the available results indicate that this approach will help to secure a better functional outcome following peripheral nerve injury and repair.

Age-related dementias such as Alzheimer disease (AD) have been linked to vascular disorders like hypertension, diabetes and atherosclerosis. These risk factors cause ischemia, inflammation, oxidative damage and consequently reperfusion, which is largely due to reactive oxygen species (ROS) that are believed to induce mitochondrial damage. At higher concentrations, ROS can cause cell injury and death which occurs during the aging process, where oxidative stress is incremented due to an accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms. Neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, causing a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondria specific antioxidants such as acetyl-L-carnitine and R-alphalipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and amyloid beta oxidation and making these antioxidants very powerful alternate strategies for the treatment of AD.