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Parkinson's disease (PD) is an idiopathic disease caused by the loss or degeneration of the dopaminergic (dopamine-producing) neurons in the brain and characterized by various inflammatory and apoptotic responses in the neuronal cells. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) axis is responsible for neuronal survival by providing a number of anti-inflammatory and anti-apoptotic milieu that prevent the progression of PD. Alpha-lipoic acid (ALA) is a natural cofactor that has antioxidant capacity and contributes to various metabolic processes. ALA can penetrate the blood-brain barrier and contribute to numerous neuroprotective effects. It can activate PI3K/AKT pathway with consequent reduction of different inflammatory and oxidative biomarkers. Our work aims to unfold the neuroprotective effects of ALA via targeting PI3k/AKT pathway. Forty male mice were divided into four groups: control, ALA (100 mg/kg/day; i.p.), rotenone (ROT) (1.5 mg/kg/2 days, i.p.) and rotenone + ALA for 21 days. ALA showed obvious neuroprotective effects via significant activation of PI3K/AKT pathway with subsequent decreasing level of Caspase-3. ALA resulted in prominent anti-inflammatory actions by decreasing interlukin-1β (IL-1β), tumor necrosis factor (TNF)-α and nuclear factor kabba (NFk)-B. ALA remarkably induced antioxidant activities via increasing reduced glutathione (GSH) and superoxide dismutase (SOD) levels as well as decreasing malondialdehyde (MDA) level. The substantial behavioral improvement reflected in these results was noticed in the ALA-treated mice as a reflection of the neuroprotective activities of ALA. In conclusion, ALA showed promising neuroprotective effects in rotenone-induced PD via activating the PI3K/AKT pathway and consequent inhibition of apoptotic and inflammatory biomarkers., Competing Interests: Declaration of competing interest none., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lipoic acid (α-LA) (1,2-dithiolane3-pentanoic acid (C 8 H 14 O 2 S 2 ) is also called thioctic acid with an oxidized (disulfide, LA) and a reduced (di-thiol: dihydro-lipoic acid, DHLA) form of LA. α-LA is a potent anti-oxidative agent that has a significant potential to treat neurodegenerative disorders. α-LA is both hydrophilic and hydrophobic in nature. It is widely distributed in plants and animals in cellular membranes and in the cytosol, which is responsible for LA's action in both the cytosol and plasma membrane. A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the α-Lipoic acid for central nervous system diseases. Moreover, α-LA readily crosses the blood-brain barrier, which is a significant factor for CNS activities. The mechanisms of α-LA reduction are highly tissue-specific. α-LA produces its neuroprotective effect by inhibiting reactive oxygen species formation and neuronal damage, modulating protein levels, and promoting neurotransmitters and anti-oxidant levels. Hence, the execution of α-LA as a therapeutic ingredient in the therapy of neurodegenerative disorders is promising. Finally, based on evidence, it can be concluded that α-LA can prevent diseases related to the nervous system., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The present study evaluates the neuroprotective effect of α-lipoic acid (ALA) and/or metformin (MET) on the behavioral and neurochemical changes induced by hypothyroidism., Methods: Rats were divided into control, rat model of hypothyroidism induced by propylthiouracil, and rat model of hypothyroidism treated with ALA, MET, or their combination., Results: Behaviorally, hypothyroid rats revealed impaired memory and reduced motor activity as indicated from the novel object recognition test and open-field test, respectively. Hypothyroidism induced a significant increase in lipid peroxidation (malondialdehyde [MDA]) and a significant decrease in reduced glutathione (GSH) and nitric oxide (NO) in the cortex and hippocampus. These were associated with a significant increase in tumor necrosis factor-α (TNF-α) and a significant decrease in brain-derived neurotrophic factor (BDNF). Hypothyroidism decreased significantly the levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and reduced the activities of acetylcholinesterase (AchE) and Na+, K+-ATPase in the cortex and hippocampus. Treatment of hypothyroid rats with ALA and/or MET showed an improvement in memory function and motor activity. Moreover, ALA and/or MET prevented the increase in MDA and TNF-α, and the decline in GSH, NO, BDNF, 5-HT, NE, and DA. It also restored AchE and Na+, K+-ATPase activities in the studied brain regions., Conclusion: ALA and/or MET has a potential neuroprotective effect against the adverse behavioral and neurochemical changes induced by hypothyroidism in rats., (© 2022 S. Karger AG, Basel.)

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

Background: Glucose fluctuation promotes neuronal apoptosis, which plays a central role in diabetic encephalopathy (DE). Nerve growth factor (NGF), and its interaction with high-affinity (TrkA) and low-affinity (p75NTR) receptors, are involved in neuronal survival. NGF/TrkA contributes to the activation of the PI3K/AKT pathway, which is beneficial for neuronal survival, and α-Lipoic acid (ALA) exerts clinically favorable neuroprotective effects in the periphery. Whether NGF receptors and the PI3K/AKT pathway are involved in glucose fluctuation-induced neuronal damage, as well as the potential molecular mechanism of ALA in protecting glucose fluctuation-induced neuronal damage, remain unclear., Results: The results indicated that constant high glucose (CHG) and intermittent high glucose (IHG) significantly increased the expression of Bax and caspase-3, and decreased the expression of TrkA/p75NTR and p-AKT/AKT, while ALA stimulation reversed the above proteins in PC12 cells. IHG stimulates apoptosis more effectively than CHG in PC12 cells, which is related to the PI3K/AKT pathway but not to the TrkA/p75NTR. Furthermore, neuronal apoptosis induced by IHG was aggravated by the TrkA inhibitor K252a or the PI3K/AKT inhibitor LY294002, but this effect was alleviated by the p75NTR inhibitor TAT-pep5., Conclusion: Glucose fluctuation induced cell apoptosis by regulating the TrkA/p75NTR and PI3K/AKT pathway, meanwhile ALA exhibited neuroprotective effects in response to IHG and CHG. These observations indicated that the PI3K/AKT pathway and the balance of TrkA/p75NTR are likely to serve as potential therapeutic targets for DE. In addition, ALA could be a possible therapeutic drug for DE.

New series of triazole-containing 3-phenylcoumarin-lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer's disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H 2 O 2 -induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC 50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ 1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H 2 O 2 -induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer's disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cognitive impairment is present in patients with depression. We hypothesized that alpha-lipoic acid (ALA) can reduce cognitive impairment, especially when combined to antidepressants. Female mice received vehicle or corticosterone (CORT) 20 mg/kg, s.c. for 14 days. From the 15th to 21st day, the animals were divided in groups: vehicle, CORT, CORT+desvenlafaxine (DVS) 10 or 20 mg/kg, ALA 100 or 200 mg/kg, DVS10+ALA100, DVS20+ALA100, DVS10+ALA200, or DVS20+ALA200. Tail suspension (TST), social interaction (SIT), novel object recognition (NOR), and Y-maze tests were conducted. Acetylcholinesterase activity (AChE) was measured in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). CORT caused depressive-like behavior, impairment in SIT, and cognitive deficits. Alpha-lipoic acid and DVS, alone or combined, reversed CORT effect on TST. In the NOR, ALA200 alone, DVS10+ALA100, or DVS10+ALA200 reversed the deficits in short-term memory, while DVS20 alone or DVS20+ALA200 reversed the deficits in long-term memory. In the Y-maze test, ALA200 alone, DVS20+ALA100, or DVS20+ALA200 reversed the deficits caused by CORT in the working memory. CORT increased AChE in the PFC, HC, and ST. ALA200 alone or DVS20+ALA200 reversed this effect in the PFC, while DVS20 or DVS20+ALA100 reversed this effect in the HC. In the ST, DVS10 or 20, alone or combined, and ALA100 reversed the effects of CORT. These results suggest that DVS+ALA, by reversing CORT-induced memory and social deficits, seems to be a promising therapy for the treatment of depression and reversal of cognitive impairment observed in this disorder.

In a model of early-stage Parkinson's disease induced by a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to Wistar rats, a neuroprotective effect of a new derivative of carnosine and α-lipoic acid (C/LA nanomicellar complex) was demonstrated. Acute intraperitoneal administration of carnosine, α-lipoic acid and C/LA complex following MPTP administration normalized the total antioxidant activity in the brain tissue. Of all the compounds tested only C/LA complex normalized the metabolism of dopamine (DA) and serotonin (5-HT), while its components did not show similar effects when used separately. C/LA complex effectively restored the level of DA metabolites: the level of DOPAC was increased by 24.7 ± 5.6% compared to the animals that had received MPTP only, and the level of HVA was restored to the values observed in the intact animals. Integral metabolic indices of DA (DOPAC/DA and HVA/DA ratios) and 5-HT turnover (5-HIAA/5-HT ratio) in the striatum tended to increase in case of C/LA complex administration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the effects of lipoic acid and methylprednisolone on nerve healing in rats with traumatic facial paralysis., Materials and Methods: The rats were randomly divided into four groups, with six rats in the control group and eight each in the remaining three groups. The buccal branch of the facial nerve in all groups except the control group was traumatized by a vascular clamp for 40 minutes. Group 1 was given lipoic acid (LA), Group 2 was given methylprednisolone (MP), and Group 3 was given lipoic acid and methylprednisolone (LA + MP) for one week. Nerve stimulus thresholds were measured before trauma, after trauma and at the end of the one week treatment period., Results: When the groups were compared with each other, post-treatment threshold levels of LA + MP were significantly lower than LA. Although post-treatment threshold levels of LA and MP were still higher than the control group, there was no significant difference between LA + MP and control values (p > .05)., Conclusion: Lipoic acid has a positive effect on nerve healing and can enhance the effect of methylprednisolone treatment. It is a good alternative in cases where methylprednisolone cannot be used.

Alpha-lipoic Acid(ALA), an endogenous short-chain fatty acid, has been found inducing a protective effect against ischemia and reperfusion(I/R) injury. Recently, mTOR signaling pathway has been proved to involve in the mechanism of I/R injury. In our previous study, we determined that ALA could protect cerebral endothelial cells against I/R injury via mTOR signaling pathway. However, whether ALA can protect against brain I/R injury in vivo and its mechanisms is uncertain. In this study, we try to explore if the ALA treatment can protect against brain I/R injury and confirm the relationship between ALA and mTOR signaling pathway. ALA was administrated to the animals after dMCAo and reperfusion model established with or without rapamycin pre-treatment. The results showed the infarct size was obviously reduced after ALA treatment in acute stage, neurological functions were also improved distinctly. The mTOR signaling pathway was remarkably blocked after brain I/R injury while it could be activated through ALA treatment. However, rapamycin, can abolish the protective effects induced by ALA treatment in both acute and long-term phase. In conclusion, we demonstrate the protective effects induced by ALA treatment against the brain I/R injury in rats and mTOR signaling pathway is required for the protective effects of ALA against brain I/R injury. The results might contribute to the potential clinical application of ALA and provide a potential therapeutic target on ischemic stroke., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/aims: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of α-Lipoic acid (α-LA) remain poorly understood. Herein, we investigated the potential role of α-LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model., Methods: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-κB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-κB., Results: Both 20 mg/kg and 40 mg/kg of α-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, α-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1β, IL-6, TNF-α and IL-10, and attenuated the activation of NF-κB after MCAO. α-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-κB in LPS-stimulated BV2 microglia., Conclusions: α-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of α-LA might be mediated by inhibition of NF-κB activation via regulating phosphorylation and nuclear translocation of p65., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: A combination of alpha-lipoic acid preconditioning (ALAP) and ischaemic preconditioning (IPC) has not been tested in an in vivo rat cerebral ischaemia/reperfusion injury (I/RI) model, and the potential protective mechanisms have not been well elucidated. The aim of this study was to investigate the role of the TLR4/ MyD88/ NF-κB signaling pathway in the synergistically neuroprotective and anti-inflammatory effects of ALAP and IPC., Methods: One hundred and fifty male Sprague-Dawley rats, weighing 180-230 g, were randomly divided into the following 5 groups: 1) sham-operated control; 2) I/R; 3) I/R+ALAP; 4) I/R+IPC; 5) I/R+IPC+ALAP. After 2 h of reperfusion, the infarct size, neurological deficit scores, brain oedema, oxidative stress, and inflammatory and apoptotic biomarkers were assessed. In addition, reactive oxygen species (ROS) and cell apoptosis were detected by DHE staining and TUNEL staining, respectively., Results: Both ALAP and IPC treatment attenuated the I/RI-induced neuronal injury, reflected by reductions in the infarct size, neurological deficit scores, brain oedema, lactate dehydrogenase (LDH) release and the inflammatory response, as well as decreased HMGB1, TLR4, MyD88, p65, C-Caspase 3 and Bax expression and increased IKB-α, HO-1, SOD-2 and Bcl-2 expression compared to that in the I/R group. Furthermore, the combination of the two strategies had synergistic anti-inflammatory effects and antioxidant benefits, ultimately limiting neuronal apoptosis., Conclusion: The 'cocktail' strategy exhibited a significant neuroprotection against I/RI by attenuating neuroinflammation via inhibition of the TLR4/MyD88/NF-κB signaling pathway., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Using our in vitro and in vivo models of oxidative stress, the current study was designed to determine the neuroprotective potential of naringenin, alone or in combination with lipoic acid. In our mixed neuronal culture exposed to hypoxia and subsequent reoxygenation, naringenin was shown to provide significant neuroprotection against cell death at a concentration of 2.5 μmol/L. Lipoic acid (LA) did not produce neuroprotection at any concentration tested (0.25-100 μmol/L). In contrast, when naringenin was covalently combined with LA, producing a novel compound named "VANL-100", significant neuroprotection was observed at a concentration as low as 2×10 -2  μmol/L (100-fold more potent). An ELISA for antioxidant capacity demonstrated that naringenin and VANL-100 likely resulted in neuroprotection by increasing the free radical scavenging capacity of the neuronal cells. Pretreatment of rats with the above compounds prior to middle cerebral artery occlusion (MCAO) followed by reperfusion, showed similar results. Naringenin significantly reduced infarct volume at a dose of 10 mg/kg while VANL-100 produced significant neuroprotection at a dose as low as 1×10 -4  mg/kg (10 000-fold more potent). This VANL-100-induced neuroprotection persisted even when administered 1 and 3 hours into the reperfusion time course. Taken together, these results suggest that our novel compound, VANL-100 is neuroprotective, likely via a mechanism that involves increasing the antioxidant capacity of neuronal cells. Our results also show that VANL-100 is 100-10 000-fold more potent than the parent compounds, which adds to the growing evidence in support of combination therapy targeting oxidative stress in neurodegenerative diseases., (© 2017 John Wiley & Sons Australia, Ltd.)

Objective: Parkinson's disease (PD) is a common neurodegenerative disease. This study aimed to investigate the effects of the R form of α-lipoic acid (RLA) in cellular models of PD induced by 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)., Methods: Cell viability and apoptosis were detected using CCK8 and Annexin V-FITC assays, respectively. Intracellular reactive oxygen species (ROS) were detected by fluorescence staining. ELISA assays were performed to detect the levels of dopamine and α-synuclein. To evaluate the effects of RLA on mitochondrial function, cytotoxicity, ATP levels, and mitochondrial gene expression were assayed. Additionally, the expression levels of autophagy-related proteins, including Parkin, PINK1, p62, ATG12, and LC3, were analyzed by western blot, and cell autophagy was visualized by immunofluorescence., Results: RLA increased cell viability and decreased apoptosis, intracellular ROS, and cytotoxicity, and induced cell autophagy in PD models induced by 6-OHDA and MPTP. RLA also reversed the decreased dopamine and increased α-synuclein expression induced by 6-OHDA and MPTP. The mitochondrial regulatory protein PGC-1α was significantly up-regulated by RLA. The expression levels of autophagy-related proteins, including Parkin, PINK1, p62, and ATG12, were down-regulated after RLA treatment, while LC3 expression was up-regulated., Conclusions: RLA has a protective effect against cellular damage induced by 6-OHDA and MPTP. The neuroprotective mechanism of RLA may be associated with improvement of mitochondrial function and autophagy. Therefore, RLA may serve as a promising potential adjuvant for PD treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background/aims: Alpha-lipoic acid (α-LA) has been demonstrated to be protective against cerebral ischemia injury. Herein, we investigate the neuroprotective effect and underlying mechanisms of α-LA., Methods: In vivo study, α-LA was administered intravenously upon reperfusion of transient middle cerebral artery occlusion. Garcia score was used to evaluate neurologic recovery. Infarct volume was examined by TTC staining, and oxidative damage was evaluated by ELISA assay. In an in vitro study, neurons were pretreated with α-LA at different doses and then subjected to OGD. Lentiviral vectors were applied to knockdown nuclear factor-erythroid 2-related factor-2 (Nrf2) or heme oxygenase-1 (HO-1). Cell viability was measured using CCK8. Protein expression was evaluated using western blot, and immunofluorescence staining was assessed., Results: α-LA significantly reduced the infarct volume, brain edema, and oxidative damage and promoted neurologic recovery in rats. Pretreatment of α-LA caused an obvious increase in cell viability and a decrease in intracellular reactive oxygen species. Western blot analyses and immunofluorescence staining demonstrated a distinct increase in Nrf2 and HO-1 protein expression. Conversely, knockdown of Nrf2 or HO-1 resulted in the down-regulation of HO-1 protein and inhibited the neuroprotective effect of α-LA., Conclusion: α-LA treatment is neuroprotective and promotes functional recovery after ischemic stroke by attenuating oxidative damage, which is partially mediated by the Nrf2/HO-1 pathway., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

MeHg is one of the environmental pollutants that lead to oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) concentration. However, little was known of the interaction. Therefore, we developed a rat model of MeHg poisoning to explore its neurotoxic effects, and whether LA could attenuate MeHg-induced neurotoxicity. Seventy-two rats were randomly divided into four groups: control group, MeHg-treated groups (4 and 12μmol/kg), and LA pre-treatment group. Administration of the 12μmol/kg MeHg for 4 weeks significantly increased ROS formation that might be critical to aggravate oxidative damages in cerebral cortex. Meanwhile, Glu metabolism as well as GLAST and GLT-1 appeared to be disrupted by MeHg exposure. Pre-treatment of the 35μmol/kg LA significantly prevented MeHg-induced oxidative stress and Glu dyshomoestasis. In conclusion, findings indicated that MeHg could induce oxidative stress and Glu uptake/metabolism disorders in cerebral cortex, LA might antagonize these neurotoxic effects induced by MeHg., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study, we investigated the combined effect of pioglitazone (PIO) with alpha lipoic acid (ALA) on the peripheral nerves of diabetic rats. Animals were divided into 8 groups (N = 6-8) and designated according to ALA (100 mg/kg/day) and PIO (10 mg/kg/day) treatment: Normal, Normal + ALA, Normal + PIO, Normal + ALA + PIO, DM, DM + ALA, DM + PIO, and DM + ALA + PIO. After 24 weeks, current perception threshold, mechanical allodynia, oxidative stresses, intraepidermal nerve fiber density (IENFD), and axonal morphology in the sciatic nerve were compared among groups. IENFD in the DM + ALA + PIO group was significantly less reduced than in other DM groups (7.61 ± 0.52 vs. 5.62 ± 0.96, 5.56 ± 0.60, and 7.10 ± 0.70 for DM, DM + ALA, and DM + PIO, respectively P < 0.05). The mean myelinated axonal area in the sciatic nerves was significantly higher in the DM + ALA + PIO group compared with non-treated DM group (70.2 ± 3.46 vs. 61.1 ± 2.91, P < 0.05) although significant differences were not present between combination therapy and monotherapy independent of ALA or PIO. Our results demonstrated that combination therapy using PIO based on ALA can give an additional benefit in peripheral nerve preservation in diabetes. Moreover, PIO can be preferentially considered when additional glucose-lowering agent is required in DPN patients treated with ALA.

Edaravone, an electron spin trapper with radical scavenging activity, has been shown to be effective in reducing infarct volume in humans following ischemic stroke. However, concerns of edaravone-induced renal toxicity have limited its clinical adoption. Previous work has demonstrated that edaravone produced significant neuroprotection when injected prior to a period of ischemia and/or reperfusion. The current investigation was designed to determine if a newly synthesized co-drug consisting of lipoic acid and edaravone, named UPEI-300, could produce neuroprotection in in vitro and/or an in vivo rodent model of stroke. UPEI-300 produced dose-dependent neuroprotection in vitro and was subsequently tested in vivo. Male rats were anaesthetized and the middle cerebral artery was occluded for 30 min followed by 5.5 h of reperfusion (ischemia/reperfusion; I/R). Pre-administration of UPEI-300 dose-dependently decreased infarct volume. Significant neuroprotection was also observed when UPEI-300 (1.0 mg/kg) was injected during the 30 min period of ischemia as well as up to 60 min following the start of reperfusion. These results indicate that a co-drug consisting of edaravone and lipoic acid is a potent neuroprotectant, and clinically, the use of such a novel co-drug following an ischemic stroke might maintain neuroprotection while potentially decreasing edaravone associated renal toxicity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The results of experimental studies and clinical trials of alpha-lipoic acid drugs are presented. Antioxidant and neuroprotective effects provide the efficacy of these drugs in patients with different diseases of the central and peripheral nervous systems. Good tolerability and possibilities of using in combinations with other drugs give grounds for a wide application of the drug in neurological practice.

Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder for which current treatments afford symptomatic relief with no prevention of disease progression. Due to the neuroprotective and anti-apoptotic potential of alpha lipoic acid (LA), this study was undertaken to evaluate whether LA could improve behavioral and cellular abnormalities and markers of oxidative stress in an experimental model of early PD in rat. Unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated p.o. with LA at doses of 50 and/or 100mg/kg twice at an interval of 24h. After 1 week, apomorphine caused significant contralateral rotations, a significant reduction in the number of neurons was observed on the left side of the substantia nigra pars compacta (SNC), and malondialdehyde (MDA) and nitrite levels in midbrain homogenate significantly increased and activity of superoxide dismutase significantly reduced in the 6-OHDA group. LA pretreatment at a dose of 100mg/kg significantly attenuated rotations, prevented loss of SNC neurons, and lowered levels of MDA and nitrite. These results suggest that LA could partially afford neuroprotection against 6-OHDA neurotoxicity that is in part due to the attenuation of oxidative stress burden and this may provide benefits, along with other therapies, in neurodegenerative disorders including PD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Alpha-lipoic acid (ALA), a natural antioxidant, is widely used for the treatment of some diseases including diabetes, and decursinol (DA), a constituent of root of Angelica gigas Nakai, has some pharmacological activities including anti-inflammatory function. In this study, we synthesized a novel synthetic alpha-lipoic acid-decursinol (ALA-DA) hybrid compound, and compared neuroprotective effects of ALA, DA or ALA-DA against ischemic damage in the gerbil hippocampal CA1 region induced by 5 min of transient cerebral ischemia. In the 10 and 20 mg/kg ALA-, DA- and 10 mg/kg ALA-DA-pre-treated-ischemia-groups, there were no neuroprotective effects against ischemic damage 4 days after ischemic injury. However, 20 mg/kg ALA-DA pre-treatment protected pyramidal neurons from ischemic damage in the CA1 region. In addition, 20 mg/kg ALA-DA pre-treatment markedly decreased the activation of astrocytes and microglia in the CA1 region 4 days after ischemic injury. On the other hand, post-treatment with the same dosages of them did not show any neuroprotective effect against ischemic damage. In brief, these findings indicate that pre-treatment with ALA-DA, not ALA or DA alone, can protect neurons from ischemic damage in the hippocampus induced by transient cerebral ischemia via the decrease of glial activation.

Previous work in our laboratory has provided evidence that preadministration of apocynin and lipoic acid at subthreshold levels for neuroprotection enhanced the neuroprotective capacity when injected in combination. Therefore, the present investigation was designed to determine whether a co-drug consisting of lipoic acid and apocynin functional groups bound by a covalent bond, named UPEI-100, is capable of similar efficacy using a rodent model of stroke. Male rats were anesthetized with Inactin (100 mg/kg iv), and the middle cerebral artery was occluded for 6 h or allowed to reperfuse for 5.5 h following a 30-min occlusion (ischemia/reperfusion, I/R). Preadministration of UPEI-100 dose-dependently decreased infarct volume in the I/R model (P < 0.05), but not in the middle cerebral artery occlusion model of stroke. Using the optimal dose, we then injected UPEI-100 during the stroke or at several time points during reperfusion, and significant neuroprotection was observed when UPEI-100 was administered up to 90 min following the start of reperfusion (P < 0.05). A time course for this neuroprotective effect showed that UPEI-100 resulted in a decrease in infarct volume following 2 h of reperfusion compared with vehicle. The time course of this neuroprotective effect was also used to study several mediators along the antioxidant pathway and showed that UPEI-100 increased the level of mitochondrial superoxide dismutase and oxidized glutathione and decreased a marker of lipid peroxidation due to oxidative stress (HNE-His adduct formation). Taken together, the data suggest that UPEI-100 may utilize similar pathways to those observed for the two parent compounds; however, it may also act through a different mechanism of action.

Lipoic acid (LA) is an antioxidant that is effective in treating experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). C57BL/6 mice with EAE develop experimental autoimmune optic neuritis (EAON), which models acute optic neuritis in humans. Here we determined whether LA is therapeutically effective in EAON. We immunized C57BL/6 mice with MOG 35-55 peptide. Mice received either daily subcutaneous injections of LA (100mg/kg) or saline in early or late suppression paradigms. In the early suppression paradigm, optic nerve cross-sections showed 14.9±3.8% (mean±SEM) damage in mice receiving saline (n=7) and 2.0±0.4% damage in mice given LA (n=7, p=0.001). In the late suppression paradigm, optic nerve sections showed 24.6±3.5% damage in mice treated with saline (n=7) and 8.4±2.5% in mice treated with LA (n=7, p=0.004). Thus a dramatic reduction in axonal injury was seen after LA administration in both experimental paradigms. Compared with saline treated mice with EAON, optic nerves from mice receiving LA had significantly fewer CD4+ and CD11b+ cells in both paradigms. This study provides a rationale for investigating the therapeutic efficacy of LA in acute optic neuritis in humans., (Published by Elsevier B.V.)

Data of literature on the role of inflammation factors in the pathogenesis of stroke are presented. The study of myeloperoxidase level in the early acute phase of ischemic stroke and dynamics of this parameter after the antioxidant treatment with the α-lipoic acid preparation berlition was carried out. It has been shown that the activation of systemic inflammation and related oxidative stress recorded in the early acute phase of brain infarction needs pharmacological treatment. Neuroprotective action of α-lipoic acid related to the prevention of damaging effect of free radicals on cell membranes and reduction of oxidative stress intensity is a pathogenetic explanation for using its preparations in ischemic brain lesions. The decrease in plasma myeloperoxidase content after the treatment with berlition may consider as a criterion of its efficacy.

Purpose: Many of the hypotheses have been suggested to explain the mechanism of the secondary effects of traumatic spinal cord injury (TSCI) as follows: ischaemia/reperfusion disability theory, free radicals theory, exitotoxicity theory, immunological destruction theory, apoptosis theory. Recently, free radicals,lipid peroxidation reactions and apoptosis theories have been much more accepted than others. In this study, possible protective effects of the alpha lipoic acid were evaluated in the traumatic spinal cord of rats., Methods: Using a well characterised weight drop technique, spinal cord contusions were formed to 48 Wistar albino rats at thoracal 8–10 level. After alpha lipoic acid and methylprednisolone were administered intraperitoneally, the spinal cord tissues were harvested for histopathological and biochemical studies., Results: Histopathological examination results showed that neither methylprednisolone nor alpha lipoic acid can play an act to decrease or block the neural tissue destruction and necrosis in hyperacute and subacute stage of the TSCI in rats. Biochemical study results showed that alpha lipoic acid was much more decreased the lipid peroxidation levels than methylprednisolone in subacute stage. However, none of the agents was changed the myeloperoxidation level in subacute stage., Interpretation: Alpha lipoic acid and methylprednisolone administrations did not alter the onset or degree of necrosis at the zone of the TSCI in rats. On the other hand, alpha lipoic acid is more effective than methylprednisolone treatment for the prevention of lipid peroxidation after spinal cord injury., (2010 Elsevier Ltd. All rights reserved.)

Purpose: Radical oxygen species produced after injury counteracts antioxidant activity and frequently causes severe oxidative stress for the tissues. Alpha-lipoic acid is a powerful metabolic antioxidant with immunomodulatory effects which provides neuroprotection. The aim of this study is to investigate the neuroprotective and anti-apoptotic effects of alpha-lipoic acid on spinal cord ischemia-reperfusion., Methods: Twenty-four adult, male, New Zealand rabbits were divided into sham (n = 8), control (n = 8), and treatment groups (n = 8). The abdominal aorta was clamped for 30 min by an aneurysm clip, approximately 1 cm below the renal artery and 1 cm above the iliac bifurcation in control and treatment groups. Only laparotomy was performed in the sham group. Twenty-five cubic centimeters of saline in control group and 100 mg/kg lipoic acid were administered intraperitoneally in the treatment group after closure of the incision. The animals were killed 48 h later. Spinal cord segments between L2 and S1 were harvested for analysis. Levels of nitric oxide, glutathione, malondialdehyde, advanced oxidation protein products, and superoxide dismutase were analyzed as markers of oxidative stress and inflammation. Caspase-3 activity was analyzed to detect the effect of lipoic acid on apoptosis., Results: In all measured parameters of oxidative stress, administration of lipoic acid significantly demonstrated favorable effects. Both plasma and tissue levels of nitric oxide, glutathione, malondialdehyde, and advanced oxidation protein products significantly changed in favor of antioxidant activity. There was no significant difference between the plasma superoxide dismutase levels of the groups. Histopathological evaluation of the tissues also demonstrated significant decrease in cellular degeneration and infiltration parameters after lipoic acid administration. However, lipoic acid has no effect on caspase-3 activity., Conclusions: Although further studies considering different dose regimens and time intervals are required, the results of the present study prove that alpha-lipoic acid has favorable effects on experimental spinal cord ischemia-reperfusion injury.

Current evidences support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimer's disease, and (R)-alpha-lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)-alpha-lipoic acid and ibuprofen via an amide bond. These new entities might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimer's disease. Our study included the synthesis of conjugates 1-3 and the evaluation of their physicochemical and in-vitro antioxidant properties. The new compounds are extremely stable in aqueous buffer solutions (pH = 1.3 and 7.4), and in rat and human plasma they showed a slow bioconversion to ibuprofen and (R)-alpha-lipoic acid. Codrugs 1-3 displayed in vitro free radical scavenging activity and were hydrolyzed more rapidly in brain tissue than in rat serum indicating that these new entities might allow targeted delivery of the parent drugs to neurons. The immunohistochemical analysis of Abeta (1-40) protein showed that Abeta-injected cerebral cortices treated with ibuprofen or compound 1 showed few plaques within capillary vessels and, in particular, Abeta (1-40) protein was less expressed in codrug-1-treated than in ibuprofen-treated cerebral cortex.

Background: Oxidative stress is a mediator of secondary injury to the spinal cord following trauma., Objective: To investigate the putative neuroprotective effect of alpha-lipoic acid (LA), a powerful antioxidant, in a rat model of spinal cord injury (SCI)., Methods: Wistar albino rats were divided as control, vehicle-treated SCI, and LA-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10 was used. Injured animals were given either 50 mg/kg LA or saline at 30 minutes postinjury by intraperitoneal injection. At 7 days postinjury, neurologic examination was performed, and rats were decapitated. Spinal cord samples were taken for histologic examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and DNA fragmentation. Formation of reactive oxygen species in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique., Results: SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in luminol CL and MDA levels, MPO activity, and DNA damage. Furthermore, LA treatment reversed all these biochemical parameters as well as SCI-induced histopathologic alterations. Conversely, impairment of the neurologic function caused by SCI remained unchanged., Conclusion: The present study suggests that LA reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, glutathione depletion, and DNA fragmentation.

Reviewed herein is the present-day literature data concerning the causes leading to the development of ischemic stroke. Special attention is drawn to the haemodynamic mechanism, of cerebral circulation impairment. Also discussed is the fed of the onset of such disorders in patients suffering from peripheral atherosclerosis during reconstructive surgical vascular interventions, in relation with a multifocal nature of the lesion. Presented are modern findings on diagnostic methods making it possible to assess autoregulatory disorders of cerebral circulation, the main causes of these impairments, as well as potential principles of correction thereof.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring cofactor for the mitochondrial enzymes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, LA has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. In addition, LA down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF and inducible nitric oxide synthase. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. In human plasma, LA exists in an equilibrium of free and plasma protein bound form. Up to 150 muM, it is bound completely, most likely binding to high affinity fatty acid sites on human serum albumin, suggesting that one large dose rather than continuous low doses (as provided by "slow release" LA) will be beneficial for delivery of LA to the brain. Evidence for a clinical benefit for LA in dementia is yet limited. There are only two published studies, in which 600 mg LA was given daily to 43 patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of up to 48 months. Whereas the improvement in patients with moderate dementia was not significant, the disease progressed extremely slowly (change in ADAScog: 1.2 points=year, MMSE: -0.6 points=year) in patients with mild dementia (ADAScog<15). Data from cell culture and animal models suggest that LA could be combined with nutraceuticals such as curcumin, (-)-epigallocatechin gallate (from green tea) and docosahexaenoic acid (from fish oil) to synergistically decrease oxidative stress, inflammation, Abeta levels and Abeta plaque load and thus provide a combined benefit in the treatment of AD.

Background: Mood disorders are associated with decrements in cognitive function, which are insufficiently treated with contemporary pharmacotherapies., Objectives: To evaluate the putative neurotherapeutic effects of the mitochondrial cofactors, L-carnitine, acetyl-L-carnitine, and alpha-lipoic acid; and to provide a rationale for investigating their efficacy in the treatment of neurocognitive deficits associated with mood disorders., Methods: A PubMed search of English-language articles published between January 1966 and March 2007 was conducted using the search terms carnitine and lipoic acid., Results: L-carnitine and alpha-lipoic acid may offer neurotherapeutic effects (e.g., neurocognitive enhancement) via disparate mechanisms including antioxidant, anti-inflammatory, and metabolic regulation. Preliminary controlled trials in depressed geriatric populations also suggest an antidepressant effect with acetyl-L-carnitine., Conclusions: L-carnitine and alpha-lipoic acid are pleiotropic agents capable of offering neuroprotective and possibly cognitive-enhancing effects for neuropsychiatric disorders in which cognitive deficits are an integral feature.

Parkinson's disease (PD), a neurodegenerative disorder, causes severe motor impairment due to loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). MPTP, a neurotoxin that causes dopaminergic cell loss in mice, was used in an animal model to study the pathogenic mechanisms leading to neurodegeneration. We observed the activation of apoptosis signal regulating kinase (ASK1, MAPKKK) and phosphorylation of its downstream targets MKK4 and JNK, 12 h after administration of a single dose of MPTP. Further, Daxx, the death-associated protein, translocated to the cytosol selectively in SNpc neurons seemingly due to MPTP mediated down-regulation of DJ-1, the redox-sensitive protein that binds Daxx in the nucleus. Coadministration of alpha-lipoic acid (ALA), a thiol antioxidant, abolished the activation of ASK1 and phosphorylation of downstream kinases, MKK4, and JNK and prevented the down-regulation of DJ-1 and translocation of Daxx to the cytosol seen after MPTP. ALA also attenuated dopaminergic cell loss in SNpc seen after subchronic MPTP treatment. Our studies demonstrate for the first time that MPTP triggers death signaling pathway by activating ASK1 and translocating Daxx, in vivo, in dopaminergic neurons in SNpc of mice and thiol antioxidants, such as ALA terminate this cascade and afford neuroprotection.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-alpha-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-alpha-enantiomer, may be effective to treat AD and related dementias.

Purpose of Review: Research conducted over the past 10 years has uncovered molecular mechanisms that are likely to be important in the early stages of Huntington's disease pathogenesis. This review summarizes the resources and strategies that are in place in order to exploit these new findings and use them to develop novel Huntington's disease therapeutics. The role that disease models will play in this process is discussed., Recent Findings: A wide variety of models of Huntington's disease have been developed including yeast, Caenorhabditis elegans, Drosophila melanogaster and mouse. These can be developed as screening assays for the identification of chemical compounds that show beneficial effects against a specific phenotype and for the cross validation of potential therapeutics. The first compounds arising through this drug development pipeline have been reported. Similarly, the preclinical screening of compounds in mouse models is being developed in a coordinated manner., Summary: Our understanding of the molecular basis of Huntington's disease is increasing at an exponential rate. Over the next few years an increasing number of potential therapeutic compounds will have been identified. It will only be possible to take a small number of these through to phase III clinical trials. The challenge will be to use the in-vivo models of Huntington's disease to best predict which of these compounds should be pursued in the clinic, to avoid depleting the patient population willing to enter into trials, and demoralizing them by conducting repeated unsuccessful trials.

There is considerable evidence suggesting that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson's disease (PD). This possibility has been strengthened by recent studies in animal models, which have shown that a selective inhibitor of complex I of the electron transport gene can produce an animal model that closely mimics both the biochemical and histopathological findings of PD. Several agents are available that can modulate cellular energy metabolism and that may exert antioxidative effects. There is substantial evidence that mitochondria are a major source of free radicals within the cell. These appear to be produced at both the iron-sulfur clusters of complex I as well as the ubiquinone site. Agents that have shown to be beneficial in animal models of PD include creatine, coenzyme Q(10), Ginkgo biloba, nicotinamide, and acetyl-L-carnitine. Creatine has been shown to be effective in several animal models of neurodegenerative diseases and currently is being evaluated in early stage trials in PD. Similarly, coenzyme Q(10) is also effective in animal models and has shown promising effects both in clinical trials of PD as well as in clinical trials in Huntington's disease and Friedreich's ataxia. Many other agents show good human tolerability. These agents therefore are promising candidates for further study as neuroprotective agents in PD.

Background: Alpha-lipoic acid (ALA) is a potent antioxidant mitochondrial coenzyme, trometamol salt of thioctic acid, shown in clinical studies to be neuroprotective and in a preliminary study to have an effect on the symptomatology of Burning Mouth Syndrome (BMS)., Methods: We were interested in extending our studies as to whether alpha-lipoic acid might improve the symptomatology in BMS and therefore carried out a larger open controlled clinical study on the effects of alpha-lipoic acid on BMS symptomatology., Results: We have examined the effects on 4 groups of 20 patients with BMS of ALA, compared with bethanecol, Biotene and placebo, and found ALA of remarkable benefit with minimal adverse effects., Conclusions: These results suggest that double-blind randomized controlled multicenter studies of ALA are indicated.

The development of transgenic mouse models of amyotrophic lateral sclerosis (ALS) allows the testing of neuroprotective agents. We evaluated the effects of five agents in transgenic mice with the G93A Cu,Zn superoxide dismutase mutation. A novel inhibitor of poly(ADP-ribose) polymerase showed no effects on survival. Desmethylselegiline and CGP3466 are agents that exert antiapoptotic effects in vitro by preventing nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase. They had no significant effects on survival in the G93A mice. Trientine, a copper chelator, produced a modest significant increase in survival. Similarly administration of lipoic acid in the diet produced a significant improvement in survival. These results therefore provide evidence for potential therapeutic effects of copper chelators and lipoic acid in the treatment of ALS.

Background: Reperfusion aggravates nerve ischemic fiber degeneration, likely by the generation of reduced oxygen species. We therefore evaluated if racemic alpha-lipoic acid (LA), a potent antioxidant, will protect peripheral nerve from reperfusion injury, using our established model of ischemia-reperfusion injury., Methods: We used male SD rats, 300+/-5 g. Ischemia was produced by the ligature of each of the supplying arteries to the sciatic-tibial nerve of the right hind-limb for predetermined periods of time (either 3 or 5 h), followed by the release of the ligatures, resulting in reperfusion. LA was given intraperitoneally daily for 3 days for both pre- and post-surgery. Animals received either LA, 100 mg/kg/day, or the same volume of saline intraperitoneally. Clinical behavioral score and electrophysiology of motor and sensory nerves were obtained at 1 week after ischemia-reperfusion. After electrophysiological examination, the sciatic-tibial nerve was fixed in situ and embedded in epon. We evaluated for ischemic fiber degeneration (IFD) and edema, as we described previously., Results: Distal sensory conduction (amplitude of sensory action potential and sensory conduction velocity (SCV) of digital nerve) was significantly improved in the 3-h ischemia group, treated with LA (P<0.05). LA also improved IFD of the mid tibial nerve (P=0.0522). LA failed to show favorable effects if the duration of ischemia was longer (5-h ischemia)., Conclusion: These results suggest that alpha-lipoic acid is efficacious for moderate ischemia-reperfusion, especially on distal sensory nerves.

Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological intervention strategies are currently available for the treatment of stroke and numerous other brain disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders.