Potential Therapeutic Agent in Psychiatric and Neurological Diseases : Alpha Lipoic Acid

Alpha lipoic acid (ALA) which is known by its antioxidant properties can lead to positive reflections through various mechanisms of action in nervous system diseases. ALA can create privileges in the treatment of neurological and psychiatric diseases through the vital features such as prevention of formation of reactive oxygen species (ROS), having a mission as a cofactor in various enzyme complexes, promotion the level of antioxidants and neurotransmitters in brain. It has also been shown to be responsible for regulation the nerve growth factor, prevention of neuronal damage and neuronal loss, and vitalization of damaged tissues. Hence, the implementation of ALA as a therapeutic substance in the therapy of neurological and psychiatric diseases is promising in the treatment of diseases. Finally, ALA can prevent diseases related with nervous system.


Introduction
Alpha lipoic acid (ALA) which is characterized by its therapeutic effects, is described as a potent antioxidant derived from octanoic acid [1].ALA which has 8 carbons containing 2 sulfur atoms in the dithiol ring structure is an essential substrate for energy metabolism of carbohydrates, proteins and fats [2].It can naturally be synthesized by a number of enzymatic reactions from octanoic acid and cysteine in the liver and supplied a limited amount by de novo catabolism for the human body [2].Except for the synthesis of a limited amount in the body, it is present in some nutritional sources, such as red meat, liver, heart, kidney, spinach, tomato, broccoli, brussel sprouts and rice bran in small quantities [3,4].The ratio of ALA naturally synthesized by human tissues is low level in the total body pool [4].Thus, ALA is regarded as an essential nutrient [2].For this reason, the possible health effects of ALA are seen only after dietary reinforcement at 600-1800 mg/day [4].Besides, It has been reported that doses of 600-2400 mg per day are safe [5].While absorption mechanism is not clearly known, it may be absorbed by multiple carriers such as monocarboxylic and sodium-dependent multivitamin carrier.Because of the confusing routes in absorption, it is considered that the absorption of ALA may be negatively affected by means of substrate competition.Moreover, it may be subject to transcriptional regulation of specific carrier proteins [4].
When the potential health effects of ALA are evaluated; its antioxidant properties have been revealed to have positive effects on many diseases such as inflammatory diseases, neurological and psychiatric diseases, obesity, diabetes and cardiovascular diseases.ALA which is accepted as a scavenger free radicals and modulating various signal transduction pathways, provides to the improvement oxidative stress parameters and reduction of inflammation in inflammatory disorders.In presence of sepsis, ALA reduces both inflammation and oxidative stress in some organs such as liver and kidney through reducing myeloperoxidase activity and lipid peroxidation, increasing superoxide dismutase activity and catalase activity [6].
While ALA is traditionally known by its antioxidant features, it has recently been suggested that ALA has therapeutic potential implications for the treatment of dyslipidemia.ALA modulates cholesterol homeostasis in many ways, including reduction of cholesterol synthesis, attenuation of bile acid synthesis, and enhancement of cholesterol clearance [7].In addition, the supplementation with ALA can cause to significant weight loss and importantly can decrease body mass index [8].Weight loss caused by ALA may restore the level of thyroid hormone levels in plasma and diminish oxidative stress and thus it is suggested that ALA may act as a therapeutic potential agent in heart diseases [9].

Potential Therapeutic Agent in Psychiatric and Neurological Diseases: Alpha Lipoic Acid
When the relationship between ALA and psychiatric disorders is examined; it is suggested that ALA have important effects on psychiatric disorders.Especially, the possible effects of ALA are evident in schizophrenia.The existance of an oxidative instability has been increasingly highlighted in pathophysiological process of schizophrenia.Thus, the use of antioxidant substances may have a powerful effect for schizophrenia treatment [22].It has been announced that ALA inhibits the inflammatory and oxidative damage induced by myeloperoxidase which is found in high concentrations in the serum of schizophrenia patients.Besides, except of inhibiting myeloperoxidase, it can promotes the regulation in gene expression and transcription of proinflammatory factors [22].ALA can also reduce oxidative stress which has been responsible for the pathogenesis of main psychiatric disorders, such as schizophrenia, bipolar disorder and major depression.Especially, major depression disorder is related to free radicals and oxidative imbalance [23] and ALA is a promising substance for the therapy of depression through enhancement of glutathione levels in the prefrontal cortex and striatum.Moreover, it reverses the decline in neurotrophic factor in the hippocampus and striatum, and reduces whole brain total nucleoside triphosphate levels [23][24][25].

Results
In this review study, thirty-four research articles related to ALA and the nervous system were examined (Table 1).Research results show that; ALA has visible and assertive effects on neurological diseases including multiple sclerosis, Alzhemier's disease, Parkinson's disease, as well as psychiatric disorders such as depression, schizophrenia, and anxiety.In addition, ALA helps to repair or prevent damage related to nervous system such as traumatic brain injury, neuronal apoptosis, neurotoxicity, spinal cord injury and neuropathy.It acts as an reputable role in the management of the nervous system diseases by its properties such as neuronal damage inhibitor, neurorestorative and nervous system supporter.

Conclusion
Although antioxidants such as ALA are known to be beneficial for our health, it is unclear how useful and effective it is in the nervous system.In particular, it is thought that it can play a role in prevention of neurological and psychiatric diseases and in reducing the reflection of diseases.In the course of the management of nervous system diseases, the necessary medical treatment together with ALA administration may alleviate the clinical reflection of neurologic and psychiatric diseases.Therefore, ALA can be shown as an effective therapeutic agent for the therapy of nervous system diseases.

Potential Therapeutic Effects of Alpha Lipoic Acid in Psychiatric and Neurological Diseases
ALA can act as a vital role for the treatment of various nervous system diseases by fighting against free radicals, acting as a cofactor in many enzyme complexes, supporting the reduction of lipid peroxidation, and regenerating damaged tissues.Because of its potent antioxidant effect, ALA can inhibit neuron damage caused by ROS manufactured throughout neurodegenerative diseases.ALA is associated with neurodegenerative diseases because of anti-inflammatory activity and behaves like a metal chelator that diminishes oxidative processes [10].Except some features like reducing lipid peroxidation and enhancing antioxidants and neurotransmitters in brain, it also supports regulation of nerve growth factor.In addition, it provides the expression of superoxide dismutase gene [11] and helps to maintain blood glucose balance as affecting the signal pathways of insulin [5].The reduction of oxidative stress and sustaining blood glucose balance by ALA can prevent neurodegenerative diseases [5].
ALA is regarded as biological thiol antioxidants which are located at the center of antioxidant defenses mechanism in nervous system tissues.Because of neuroprotective effects, it is thought to be a therapeutic agent in a lot of neurotraumatic models [12].ALA exerts a definite protective effect on the tissues and thus may resist neurotoxicity.It also have anti-apoptotic influences on hippocampal neurons.Especially, it provides to the inhibition neuronal apoptosis by means of Caspase 3 pathway and NF KappaB dependent pathway [13].ALA decelerates the brain atrophy rate, reduces demyelination and axonal loss in spinal cords, stabilizes blood-brain barrier, and improves the progression of multiple sclerosis.Therefore, ALA has been recomended for clinical benefit in multiple sclerosis [14][15][16].
Chronic administration of ALA supplementation supports cognitive function and memory.It has been proven that the supplemention of ALA improves cognitive function by increasing total antioxidant capacity, decreasing peripheral oxidative damage, and reducing neurodegeneration in the hippocampal region [5].Besides, ALA has a potential role in cognitive and behavioural functions via the enhancement of the cholinergic process.Thus, it is an desirable curative agent for the cure of neurvous system disorders [17].ALA has been demonstrated to have a mechanism of action interfered with pathogenic results of Alzhemier's disease which is also characterized by both a cholinergic deficit, and senile plaques (accumulation of betaamyloid).ALA can be a therapeutic candidate for the treatment of Alzhemier's disease through protecting neurons from betaamyloid neurotoxicity and inhibiting the formation of betaamyloid fibrils [18].It greatly improves cerebral damage, preserves the cortical neurons, and inhibits inflammatory responses and oxidative stress [19] ALA (100mg/kg/day) inhibited behavioral impairments accompanied by hippocampal oxidative alterations, possibly related to NMDA receptors hypofunction, demonstrating a beneficial effect as antipsychotic agent. [22]

Traumatic brain injury
Traumatic brain injury weight-drop model in male rats ALA (20 or 100 mg/kg) enhanced neuronal survival by the downregulation of caspase-3 expression.In addition, it diminished malondialdehyde level, Bcl-2-associated X protein, and glutathione peroxidase activity.Thus, ALA heals neurological results and inhibits apoptosis by a action related to mitochondria.
[1] Schizophrenia Adult male Swiss mice induced by ketamine.
ALA (100 mg/kg) assumed a antipsychotic role via reversing behavioral alterations by the mechanism of neurotrophic and nitrergic pathways.Besides, the administration of clozapine together with ALA improves most of the parameters without causing motor impairment. [26]

Stroke
Adult male Sprague-Dawley (n=201) induced by clinical stroke ALA implementation was responsible for decreased mortality, reduced infarction, reduced neurological deficit score.Besides, it caused the rise in count of cells in the borderline (more double-labeled cells) and infarct nucleus regions.Moreover, it was demonstrated that the brain metabolism in ALA group markedly improved.The implementation of ALA for ischemic injury treatment has important restorative effects on neurons due to insulin receptor activation. [27]

Memory
Aluminium induced neurotoxicity in BALB/c mice (n=24) ALA (25 mg/kg/day) caused a significantly rise in the expression of muscarinic receptor genes and choline acetyltransferase comparative to the control group.ALA improved fear memory and social novelty preference comparative.ALA remarkably repaired to the fear extinction memory. [17]

Depression
Depression model in male Swiss mice (n= 295) The administration of mirtazapine combined with ALA reversed behavioral and oxidative alterations such as anxiety and depression via their central antioxidant effects. [28]

Memory Albino Charles-Foster rats
The antioxidant supplement which contains ALA prevented age-dependent alterations in synaptosomal parameters.The age-dependent deficit of learning and memory functions was remarkably prevented through antioxidant supplement which contains ALA. [29] Alzheimer's disease 11 month old SAMP8 mice ALA (100 mg/kg/day) ameliorated memory in the test of object-place recognition paradigm, and also improved learning in the Barnes maze test.It resulted significantly rise in glutathione levels, and decline glutathione peroxidase and malondialdehyde.ALA reversed oxidative stress in the brain tissue.
[30] Dementia Dementia model in adult male Wistar rats ALA (50 mg/kg/day) has potential therapeutic effects on dementia via behavioral alterations, protection of oxidative stress, and restoration of cholinergic pathway.ALA elevated acetylcholine and choline acetyltransferase level, and also reduced the action of acetycholinesterase. [31]

Schizophrenia model in male Wistar rats
The administration of ALA potentiated the inhibitory effects of chlorpromazine on gamma low-band oscillations.The alterations on EEG induced by ketamine were prevented by ALA. [32]

Depression Depression model in Swiss mice
ALA reversed the decline of the hippocampal glutathione and also it improved glutathione levels in the prefrontal cortex and striatum.ALA can take place as a promising substance for the therapy of depression. [23]

Spinal cord injury
Spinal cord injury model in male Wistar albino rats ALA (50 mg/kg/day) conversely altered histological and impairment of functions such as contraction and relaxation caused by spinal cord injury via its antioxidant and antiinflammatory actions, however, It did not improve neurological functions. [12] Alzheimer's disease Male Wistar rats ALA is an impressive candidate for the enhancement of cognitive functions and healing neurochemical defects in Alzhemier's disease via improving neuronal insulin resistance and neuronal insulin signalling.In addition, ALA assists cognitive function. [3]

Neuronal apoptosis and neurotoxicity
Neonatal mice ALA demonstrated an significant anti-apoptotic effect on hippocampal neurons.Thus, it may be an ambitious candidate for intervention against neuronal damage. [13]

Multiple sclerosis
Multiple sclerosis patients aged 40-70 years ALA which known as a slowing the brain atrophy rate proved a 68% reduction in annualized percent change brain volume.Furthermore, using of ALA for over 2 years has been recomended for clinical benefit in secondary progressive multiple sclerosis. [14]

Multiple sclerosis Multiple sclerosis model in SJL mice
ALA significantly prevented clinical alterations based multiple sclerosis via reducing demyelination, axonal loss in spinal cords, CD3+ T cells, and inflammation.[16] Multiple sclerosis Lewis rats Because of influencing the migration capacity of monocytes and balance of the bloodbrain barrier, ALA should be considered as an strong therapeutic substance for the management of multiple sclerosis. [33]

Multiple sclerosis 52 multiple sclerosis patients
While the implementation of ALA (1200 mg) resulted in an enhancement of total antioxidant capacity, whereas it did not positively affect oxidative stress parameters. [34] Table 1 The studies examining the therapeutic effects of alpha lipoic acid in nervous system diseases.
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Multiple sclerosis 52 multiple sclerosis patients
While the levels of INF-γ, TGF-β, IL-4 and ICAM-1 were significantly decreased by ALA (1200 mg) whereas the levels of EDSS, TNF-α, IL-6, and MMP-9 did not significantly alter in the patients of multiple sclerosis.[35] Multiple sclerosis 39 multiple sclerosis patients ALA demonstrated an improvement the progression of multiple sclerosis by significantly reduction EDSS in the patients which EDSS is more than zero.[15] Parkinson's disease Early Parkinson's disease model in rat ALA (100mg/kg) significantly alleviated alterations related with neurodegeneration by preventing loss of neurons, and decreasing MDA and nitrite.Thus, ALA can afford neuroprotection against neurotoxicity via attenuation of oxidative stress. [36] Parkinson's disease Male C57BL6J and Swiss albino mice ALA terminates the cascade which mitochondrial permeability transition pore triggers death the signal pathway by activation apoptosis signal regulating kinase such as ASK1 and translocating Daxx.Thus, ALA can afford neuroprotection in dopaminergic neurons. [37] Parkinson's disease PC12 cell cultures ALA protects dopaminergic neurons from oxidative damage via inhibiting development of ROS levels and reducing mitochondrial transmembrane permeability which held responsible for pathogenesis of Parkinson's disease. [21] Spinal cord injury Spinal cord injury model in rats ALA therapy reversed all of histopathologic alterations and biochemical parameters in spinal cord injury.It reduced oxidative stress and also provided neuroprotection by limiting lipid peroxidation and DNA fragmentation. [38] Spinal cord injury 48 Wistar albino rats Histopathological examination results showed that ALA did not prevent necrosis and destruction of neural tissue.[39] Cerebral ischemia Cerebral ischemia/ reperfusion model in male rats ALA attenuated oxidative stress and apoptosis.Hence, it protected cerebral damage.
Moreover it has demonstrated neuroprotective action via activation of the BDNF-PI3K/ Akt-ERK1/2 pathway. [40] Parkinson's disease PC12 cell culture ALA protected dopaminergic neurons against neurotoxicity through up-regulation of DNA repair protein. [20] Alzheimer's disease Wistar rats The implementation of an antioxidant suplement that contains ALA substantially inhibited to deterioration of spatial learning and memory in elderly rats.In addition, ALA alleviated the age-related clinical alterations in amyloid beta metabolism. [41] Parkinson's disease

Human neuroblastoma cell line SH-SY5Y
While R form of ALA upregulates mitochondrial regulatory protein PGC-1α, whereas it downregulates the autophagy-related proteins except LC3 expression.Hence, ALA has neuroprotective mechanism with prevention autophagy and the amelioration of mitochondrial function. [42] Alzheimer's disease ApoE-4 transgenic mice The R form of ALA and acetyl-L-Carnitine healed cognitive function in spatial memory and temporal memory tests. [43]

Bipolar depression 40 patients with bipolar depression
The phosphocreatine levels in the parieto-occipital cortex was reduced by ALA suplementation (600-1800 mg/day).The Montgomery-Asberg Depression Rating Scale scores of patients which treated with ALA reduced and these alterations was associated with decline in whole brain total nucleoside triphosphate levels from baseline.
[25] Depression Depression model in female Swiss mice ALA (200 mg/kg) showed an antidepressant-like effect by decreasing the preference of sucrose and reversing immobility time in the forced swimming test.It also reversed corticosterone-induced decrease in neurotrophic factor in the striatum and hippocampus. [24] Traumatic brain injury 42 Wistar albino rat pups ALA therapy significanttly decreased neuronal loss in the hippocampus, parietal cortex and prefrontal cortex.[44] Neuropathy Neuropathy model in 40 male rats ALA therapy improved brain enzymatic biomarkers and also attenuated lipid peroxidation in neuropathic rats.Besides it increased antioxidant activities in neuropathic rats.