Introduction

Alpha-lipoic acid (α-LA) is an essential antioxidant derived from octanoic acid’s energy metabolism. Due to its versatile nature and numerous therapeutic properties, it has gained the attention of researchers globally. α-LA is considered as a vital nutrient due to which its health effects are perceived after an increase in diet (600–1800 mg/day), and 600–2400 mg/day is considered a safe dose. α-LA is present in both plants and animals, and high concentration is found in tomatoes, spinach, broccoli (plant sources), liver, kidney, heart (animal sources) (Fig. 1). α-LA contains “8 carbons with 2 sulfur atoms in dithiol ring”. In the liver, α-LA can be synthesized naturally via several enzymatic reactions from octanoic acid and cysteine [1].

Fig. 1
figure 1

The Brief description showing alpha-lipoic acid (α-LA), via inhibiting oxidative damage and chronic inflammation, can be an essential therapeutic agent in treating neurodegenerative disorders. The figure also shows where the α-LA is present in the highest concentration with respect to plant and animal sources

Full size image

α-LA is absorbed via various carriers, including monocarboxylic and sodium-dependent multivitamin carriers. Due to these multiple absorptive routes, α-LA absorption may be affected by substrate competition and subject to transcriptional and post-transcriptional regulation of specific carrier proteins. The oxidized and reduced forms of dihydrolipoic acid (DHLA), both of which are antioxidants and anti-inflammatory agents, are responsible for the effects of α-LA on the cellular mechanism (Fig. 2) [2, 3]. It works by inhibiting neuron damage, removing free radicals, regulating nerve growth factor (NGF), reducing lipid peroxidation, and preventing T lymphocytes and monocytes from migrating into the CNS [3, 4].

Fig. 2
figure 2

α-LA shows its biological activity via acting as anti-carcinogenic, anti-apoptotic, anti-mutagenic, and anti-clastogenic

Full size image

Recently, α-LA attracted enormous attention in neurodegenerative disease management as a potential therapeutic option. The present review is focused on the role of α-LA in various neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), stroke, multiple sclerosis, epilepsy, and spinal cord injury (SCI) [5]. In these neurodegenerative disorders, the disease’s progression starts from subsequent energy deficiency and mitochondrial dysfunction in the disease’s early stages [6]. In earlier studies, α-LA was found to have a protective effect on the mitochondria. Indirectly, α-LA boosts mitochondrial biogenesis and improves the antioxidant system [7].

Furthermore, because of its ability to regulate specific genes encoding Nrf-2 and NF-κB, α-LA is referred to as a pleiotropic molecule. The mechanisms of action of α-LA indicate that it acts indirectly on the activation of signal transduction pathways [8] via interactions with second messengers, such as cyclic adenosine monophosphate (cAMP). α-LA causes an increase in cAMP via inhibiting the release of proinflammatory cytokines such as IL-2, TNF-α, and IFN-γ. Moreover, cAMP encourages the production of an anti-inflammatory cytokine (IL-10) which is responsible for chemokines, cytokine receptor inhibition, inflammatory mediators inhibition induced by lipopolysaccharide (LPS). cAMP activates protein kinase A (PKA) by attaching to its regulatory subunits, releasing the catalytic subunits from inhibition, and allowing phosphorylation of a variety of downstream substrates. Because of the enormous variety of ligands and GPCRs available, cAMP regulates many physiological and pathological processes through activating PKA [9]. α-LA action on NF-κB also affects inflammatory mediators expressions, which includes PGE2, iNOS, COX-2, IL-1β, TNF-α, and IL-6 [9,10,11]. Activation of NF-κB comprises ubiquitination and phosphorylation under inflammatory response. The epigenetic mechanisms, such as dysfunction of histone acetylation, DNA methylation, and miRNAs regulation, play a vital role in neurodegenerative disorders pathology [12]. The precise mechanisms by which α-LA acts on direct or indirect epigenetic regulatory pathways remain unknown. Thus, a better insight into the mechanism of action of α-LA may influence the development of more efficient therapies for neurodegenerative disorders.

Materials and methods

A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out with the keywords “Alpha-lipoic acid, neurodegenerative disease diseases, Neuroprotection, Dihydrolipoic acid, Mitochondrial dysfunction, Oxidative stress.” The review was conducted using the above keywords to collect the latest articles and understand the Nature of the extensive work done on α-Lipoic acid in neurodegenerative diseases.

De Novo Synthesis of α-LA and Itsitsnctions

α-LA, also known as thioctic acid or 1,2-dithiolane-3-pentanoic acid, contains a single chiral center and is found in both forms, i.e., R-&S-enantiomers. On the other hand, only R-LA is amide linked to conserved lysine residues, making it an essential cofactor in biological systems [5]. In human cells, fatty acids are synthesized de novo in the cytoplasm by fatty acids synthesis type 1 (FAS-I) and in the mitochondria by fatty acids synthesis type 2 (FAS-II) [13]. The human body can only produce a finite amount of α-LA via de novo catabolism, which is why α-LA should be considered an essential nutrient. α-LA is involved in Proteins’ energy process, carbohydrates, and fats metabolism because of its fat- and water-soluble properties. On the other hand, α-LA is also considered a unique antioxidant scavenging almost all forms of free radicals (oxygen and nitrogen) due to its sulfur content structure. DHLA (reduced form of α-LA) tends to restore vitamin E, glutathione, and ascorbate from these radical forms. DHLA potentially increases choline acetyltransferase (ChAT) activity, essential for cognitive functions and neuronal homeostasis [5]. The biological effects of α-LA are also associated with its anti-mutagenic and anti-carcinogenic activities [2, 14] (Fig. 3).

Fig. 3
figure 3

Figure describing the role of α-LA as anti-oxidant, anti-inflammatory, and metal chelator; NF-κβ (nuclear factor kappa-light-chain-enhancer of activated B cells); NDD (Neurodegenerative Disease); TNF-α (Tumor Necrosis Factor); IL-6 and IL-1β (Interleukin); ROS (Reactive Oxygen Species); Cu (Copper); Fe (Iron)

Full size image

Lipoid Acid and neurodegenerative Diseases

α-LA has gained much attention as a nutritional supplement with promising therapeutic benefits in treating or preventing various diseases, including neurodegenerative diseases. α-LA has been found to reduce mitochondrial dysfunction while protecting against cognitive dysfunction associated with neurodegenerative diseases. Thus, this section will summarize and discuss key findings supporting the use of α-LA as an adjuvant in treating neurodegenerative disorders via different signalling pathways.

Parkinson’s disease

The pathogenesis of PD depends on the dopaminergic neurons relapse in the substantia nigra pars compacta causing reduction of dopaminergic terminals in the striatum. Excessive levels of free radicals in Parkinson’s or dopamine and melanin auto-oxidization to reactive free radicals may result in the occurrence of oxidative reaction [15]. The mechanism behind augmented oxidative stress is mitochondria dysfunction, making the cells prone to external toxins. Studies showed that mitochondria could be a promising target to lead the therapeutic approach in neurodegenerative disorders, including PD. α-LA is considered a mitochondrial nutrient, and based on this, a study showed effective results of prevention of mitochondrial dysfunction on combined pretreatment of α-LA and acetyl-L-carnitine in a cellular model of PD [16] via decreased complex I activity, ATP production, and mitochondrial membrane potential. In the early stages, motor symptoms like rigidity, tremor, and bradykinesia occur due to neuronal deficit in the nigrastratum region. Later, it may progress to slow voluntary activities declined voice volume. It has also been known that mitochondria have a crucial role in the apoptotic cell death pathway via ‘death agonists’ such as Bax. Therefore, oxidative stress and mitochondrial dysfunction might change the threshold of apoptotic pathways activation in responses to Bax and other various pro-apoptotic molecules [16, 17]. Mitochondrial dysfunction leads to impaired energy metabolisms which remove cells susceptible to weak excitotoxicity, causing alterations in the “energy-dependent cell membrane potential.”

Further, this excitotoxic injury might increase free radical generation enhancing cellular damage. Studies revealed that antioxidants improved mitochondrial function and exerted neuroprotective effects against neurodegenerative disorders. Another critical role of α-LA in PD has been its ability to alter monoamine concentrations across the brain, which could have therapeutic implications in neurodegenerative disorders such as PD [18]. It is well established that oxidative stress contributes to dopaminergic degeneration in Parkinson’s disease (PD). In general, areas of the brain that are high in catecholamines (CA) are more vulnerable to ROS action. α-LA stimulates the release of noradrenaline and dopamine by encouraging release or decreasing the rate of monoamine metabolism and altering the acetylcholine concentration by increasing acetylcholinesterase activity. Dopamine metabolism via “monoamine oxidase or auto-oxidation” resulted in the production of hydrogen peroxide, which caused inflammation and ROS-induced tissue injury [19]. Since α-LA has demonstrated antioxidant activity, it may be pharmacologically helpful in managing neurodegenerative disorders involving oxidative stress, such as Parkinson’s disease. In various studies, it has been seen that α-LA acts by attenuating oxidative stress, enhancing norepinephrine, serotonin, and dopamine levels, providing neuroprotection [20]. α-LA was proven effective in the MPTP mouse model of Parkinson’s disease via inhibiting the activation of the apoptotic signalling cascade and the translocation of Daxx (death-associated protein) in the ventral midbrain and striatum, thereby preventing dopaminergic cell loss [21].

α-LA provides partial neuroprotection against 6-OHDA neurotoxicity, partly due to reducing oxidative stress burden and inhibiting the AMPK/mTOR autophagy pathway [22]. This, in combination with other therapies, may be beneficial in neurodegenerative disorders such as PD [15]. α-LA increased the number of neurons in the SNpc of parkinsonian rats treated with rotenone, protected dopaminergic neurons from degeneration, and decreased α-synuclein deposits in the substantia nigra (SN). Additionally, the authors demonstrated that α-LA inhibited the stimulation of nuclear factor- κB (NF-κB) and the expression of pro-inflammatory cytokines in M1 microglia [23, 24]. Overall, it has been seen that α-LA can be used as an effective treatment in PD.

Alzheimer’s disease

AD is characterized by progressive loss of cognitive functions, including memory, reasoning, and language, during daily social activities. Alzheimer’s disease causes dementia and mainly affects middle to old-aged individuals [24, 25]. Although the exact mechanism underlying AD’s pathogenesis has yet to be discovered, several hypotheses have been proposed to justify its origin. According to the previous studies known as the amyloid cascade hypothesis, in the pathological cascade of AD, clustering of A-beta peptides in amyloid plaques is the very first step. Hyperphosphorylation of the tau protein and β-amyloid peptide deposits (Aβ) is amongst those recognized in the scientific milieu [26]. Aβ buildup activates immune system cells, promoting inflammatory cytokines production, oxidative stress, and an increase in Aβ production, resulting in a vicious cycle that lasts the rest of the person’s life [27]. Increased oxygen consumption, polyunsaturated fat content, low regenerative capacity, and low antioxidant concentration contribute to brain tissue’s oxidative damage [23, 28]. As per the oligomer hypothesis, it has been seen that AD begins with synaptic dysfunction caused by soluble A-beta oligomers, resulting in changes in neurotransmitters and the cholinergic system. These alterations include disrupting basal cholinergic neurons in the forebrain cortex and decreased acetylcholine production. Acetylcholine synthesis has been impaired by glucose depletion in AD brains since acetylcholine metabolism was correlated with the glycolytic pathway and pyruvate formation [29]. Thus, oxidative stress and energy depletion are vital biochemical hallmarks of the disease. According to these findings, α-LA may also be capable of directly increasing the concentration of the substrate acetyl-CoA required for Ach synthesis [30]. In AD progression, Oxidative stress to brain tissue leads to free radical superoxide, further resulting in neuronal damage. The evaluation of oxidative stress and tissue damage markers could indicate this pathology’s progression and severity [31].

Ibuprofen and lipoic acid (IBU-LA) treatment have the potential to keep a high neuroglobin (Ngb) level in an AD model, enabling Ngb to perform either its neuroprotective function, via p-Akt and p-CREB activation, or its anti-apoptotic effect, by affecting the mitochondrial apoptotic pathway. It thus supports a valuable tool in therapeutic strategy to slow AD progression. LA is thought to interfere with AD pathogenesis, including by increasing acetylcholine (Ach) production via activation of choline acetyltransferase (ChAT) and by increasing glucose uptake. LA’s are related to its antioxidant properties and involved in scavenging of reactive oxygen species (ROS), thereby increasing the levels of active reduced glutathione; scavenging lipid peroxidation products, such as 4-hydroxynonenal (HNE) and acrolein (prop-2-enal); and downregulation of redox-sensitive pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-) and inducible nitric oxide (iNO) via NF-κB and upregulation of phase II enzymes via NRF-2 [32, 33]. LA is an essential supplement for restoring brain glucose metabolism, which is involved in the upregulation of GLUT3, GLUT4, VEGF, OGG1/2, MTH1, and HK activity in the AD via BDNF/TrkB/HIF-1 pathway [34]. In terms of treatment, antioxidants and oxidative stress biomarkers could estimate clinical outcomes and benefits. However, there is not much data on using biomarkers in AD described as predictors of clinical outcomes or severity [35]. α-LA appears to enhance the PI3K/Akt pathway of insulin signaling and alter synaptic deficits in Alzheimer’s mouse models [36, 37]. In the brains of elderly rats, Pd-LA improved mitochondrial energy status. The research also supports Pd-LA as adjunctive therapy in people with mild or moderate dementia caused by Alzheimer’s disease and standard cholinesterase inhibitors [38]. As a result, α-LA may be considered for augmentation therapy in Alzheimer’s disease.

Stroke

Stroke is the leading cause of long-term disability in developed countries, affecting millions of people [39]. Stroke is recognized as an abrupt loss of neurologic function due to a disruption in cerebral blood flow caused by hemorrhage or ischemia. The lack of oxygen and glucose in the brain can cause neurons to be unable to synthesize ATP, resulting in brain ischemia [40, 41]. Failure in ATP synthesis causes neuronal death through several congregating mechanisms, e.g., oxidative stress. According to previous research, oxidative stress is the major cause of brain injury in stroke and reperfusion following stroke [39, 41]. α-LA was given intravenously after reperfusion of a transient middle cerebral artery occlusion, showing a decrease in infarct size, oxidative damage, and brain edema while promoting neurologic recovery. α-LA helps treat and promote functional recovery after ischemic stroke by reducing oxidative damage, partly mediated by the Nrf2/HO-1 pathway [42, 57]. Both α-LA-Pretreatment and IPC therapy reduced neuroinflammation by inhibiting the TLR4/MyD88/NF-κB signalling pathway, resulting in substantial neuroprotection against IRI [43]. Under pathological conditions, the brain was highly susceptible to ROS, which causes damage due to reduced antioxidants, increased peroxidizable lipids, iron levels, and high oxygen uptake that function as pro-oxidants [44]. ROS overproduction continues even after ischemia when blood flow resumes, and brain oxygen tension rises. Therefore, ROS is considered one of the most critical components of tissue injury after reperfusion of an ischemic organ [39]. Oxidative stress resulting from ROS in brain hemorrhage ischemia and reperfusion contributes to stroke-induced neuronal death” thru both apoptosis and necrosis.

Many agents were identified as a neuroprotective therapeutic strategy for brain injury, such as Alpha-lipoic acid (α-LA) [45]. α-LA is an antioxidant frequently used to manage neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease [21, 35, 36]. α-LA impacts various cellular processes, including free radical scavenging, endogenous antioxidant regeneration, recycling, metal chelation, and transcription factor activity variation [46]. α-LA was achieved by restoring the phosphorylation of Akt and GSK3-β levels in the hippocampus. α-LA reduced cerebral ischemia and reperfusion-induced damage in adult rats by triggering the PI3K/Akt signalling pathway when given for three days [47]. In a triple transgenic mouse model of AD (3xTg-AD), α-LA improves cognitive glucose uptake, stimulates the insulin receptor substrate and the PI3K/Akt signalling pathway, counteracting the impaired synaptic plasticity and growing input/output and long-term stimulation (LTP) [48]. α-LA has been shown to improve endothelial function, blood flow, and glutathione synthesis and play a key role in regulating antioxidant and anti-inflammatory gene expression in studies [7, 49]. α-LA rescued cortical neurons from damage caused by Aβ peptide- and hydrogen peroxide, implying that the neuroprotective effects were partially attributable to activation of the PKB/Akt signalling pathway [50, 51]. Recent research suggests that calcium may play a role in the neuroprotective effects of α-LA in ischemia/reperfusion. Due to ischemia, an increase in IC calcium level might have a significant role in neuronal damage. In cortical neuronal cells, α-LA has been shown to increase resting Ca2+ levels and decrease the Ca2+ rise elicited by glutamate [39]. It has been seen that after ischemic injury, instant α-LA treatment (20 mg/kg) had long-term (56 days) neuro-restorative effects against neural damage [52]. The neuroprotective effects of α-LA pretreatment for ischemic injury have been shown in several different experimental models of MCAO in rodents [51, 53,54,55,56].

Multiple sclerosis

Multiple sclerosis (MS) is a multifactorial neurodegenerative disease in which both inflammatory and neurodegenerative processes occur simultaneously, with inflammation decreasing while CNS deterioration progresses [58]. Apoptosis and excitotoxicity linked to calcium, glutamate overload, proteolytic enzyme production, ionic channel dysfunction, and mitochondriopathy are all factors in the progression of CNS complications in MS. Mitochondrial dysfunction results in ROS overproduction, further causing damage to neurons and glia [59, 60]. Oxidative stress also damages the mitochondria causing disruption of the ATP transport along the axon leading to neurological disorder [61,62,63,64,65,66]. The inflammatory component is essential due to axonal and neuronal loss and the fact that it initiates the degenerative cascade in the primary stage of MS [67]. Inflammatory processes are affected by the activation of mitochondrial dysfunction and microglia. Microglia activated by T-lymphocytes release proteolytic enzymes, cytokines, oxidative products, and free radicals. However, microglia also have many protective properties, such as neuroprotection, lowering of the inflammatory response, and stimulation of tissue repair [68,69,70]. It’s worth noting that the procedure is convoluted and poorly understood. The treatment aims to reduce inflammation, which is possible when free radicals are neutralized. There is a need for the course to reduce disease severity and cause faster diminution and less neuroinflammation [71]. α-LA as a dietary supplement helps suppress and treat the animal model of MS [72,73,74,75]. α-LA is an antioxidant, and the primary outcome is to focus on “disease-modifying therapy” in MS experimental and clinical trials (Table 1). α-LA has shown its neuroprotective effects and the capability to cross through BBB and suppress monocytes infiltration into CNS via “reducing the migration of monocytes and improving BBB stability” against oxidative stress attacks.

In conclusion, α-LA appears to benefit molecular mediators and inflammatory and antioxidant markers. α-LA may prove helpful in treating MS by inhibiting MMP-9 activity and interfering with T-cell migration into the CNS [76, 77]. Also, they determined the pharmacokinetics (PK), tolerability, and effects on matrix metalloproteinase-9 (MMP-9) and soluble intercellular adhesion molecule-1 (sICAMP-1) of oral α-LA in patients with MS [78, 79].

Spinal cord injury

SCI is characterized by the initial, primary injury resulting from secondary injury processes involving complex biochemical, molecular, and cellular changes and even more extensive damage [80, 81]. The secondary events, accompanied by SCI, include microvascular ischemia, oxidative stress, excitotoxicity, ion imbalance, and inflammation [81]. A growing body of evidence suggests that oxygen-free radicals play an essential role in progressive spinal cord degeneration after spinal injury [82,83,84,]. In this line, a study conducted in the animal model of SCI found that increased ROS production is an early and likely causal event that contributes to the spinal cord motor neuron death following SCI. Moreover, LA reduced SCI-induced oxidative stress and demonstrated its neuroprotection by inhibiting lipid peroxidation, glutathione depletion, and DNA fragmentation. Impaired mitochondrial function occurs rapidly and may occur due to the rapid accumulation of high levels of intracellular Ca2+ observed following traumatic injury. As a result, ROS are formed that can impair the function of several cellular components, such as lipids, through oxidative mechanisms. The cytotoxic consequences of lipid peroxidation have led to the development of therapeutic strategies utilizing lipid antioxidants [85,86,87,88,89,90,91,92,93,94].

Epilepsy

Epilepsy is a chronic brain disease evidenced by temporary central nervous system dysfunction caused by the paradoxical neuronal discharge. Epilepsy’s pathogenesis is hugely complex and has not been completely elaborated. Epilepsy is caused by abnormal neuronal discharge, which can be induced by various factors, including excitatory glutamate toxicity, oxidative stress injury, and intracellular calcium overload [95]. It is widely believed that neuronal damage is caused by a chain reaction of oxygen-free radicals triggered by oxidative stress [95]. Previous research has established a strong correlation between the level of Nrf2 expression and epileptic seizures. When cells are stimulated exogenously, such as by oxidative stress, Nrf2 is released from Keap1 and transferred to the nucleus. It combines with the ARE, thereby inducing the transcription of antioxidant genes [96]. α-LA possesses a high resistance to oxidative stress, thereby protecting various cell types from apoptosis [97]. α-LA has been shown to facilitate Nrf2-mediated ARE pathway activation and HO-1 induction in human retinal pigment epithelium [98]. Recent epilepsy treatments may rely on increasing Nrf2 protein expression as Nrf2 is present in the cell plasma under normal physiological conditions, covalently linked to the Kelch-like ECH-associated protein 1 (Keap1) [96, 99,100,101]. α-LA has been shown to reduce the number of epileptic seizures and improve behavioral and cognitive disorders in rats exposed to pentetrazol. α-LA reduced nerve cell apoptosis and ameliorated neurological deficits by increasing Nrf2 expression (Fig. 4). The study also indicated that α-LA might be a choice for neuroprotection in epilepsy therapy [102].

Fig. 4
figure 4

Figure Summarizes the role of α-LA in the pathophysiology of different neurodegenerative disorders via different signaling pathways; I.C. (Intracellular); Nrf-2 (Nuclear factor erythroid 2-related factor 2); Ach (Acetylcholine); BBB (Blood brain barrier); Co-A (Coenzyme A); MAO (Monoamine oxidase); Conc. (Concentration); AD (Alzheimer’s Disease); MS (Multiple Sclerosis); SCI (Spinal Cord Injury); PD (Parkinson’s Disease); NF-κβ (nuclear factor kappa-light-chain-enhancer of activated B cells)

Full size image
Table 1 Clinical Data shows the current status of different neurodegenerative diseases
Full size table

Proteomic analysis on neurodegenerative disease

Proteomics is the study of protein levels, functions, and interactions on a large scale. It has been widely used in basic science and shows promise in clinical research, particularly in disease diagnostics [102, 103]. However, proteomics of the brain remains challenging due to the brains’ multiple regions with distinct functions. This section summarizes the proteins expressed differently and/or less oxidized in the mouse brain treated with α-LA. α-LA improves learning and memory by lowering protein oxidation and lipid peroxidation in the brains of SAMP8 mice (aged-normal mice) [102]. Proteins such as DRP-2, α-enolase, LDH, CK, and NF-L are protected by α-LA injection. The reduction of specific carbonyl levels and the increase in protein levels of specific proteins are linked to improved learning and memory in α-LA-treated SAMP8 mice. It has been suggested that oxidation of a-enolase may be responsible for the reduced levels of ATP production and acetylcholine concentration [104, 105]. By decreasing oxidative modification and increasing a-enolase protein levels in SAMP8 mice, α-LA injections imply that a-enolase activity can be preserved. A decrease in LDH carbonyl levels after injection of α-LA into SAMP8 mice suggests that α-LA treatment may help restore LDH’s ability to produce lactate in older SAMP8 mice.

As a result, in older SAMP8 mice, increased LDH activity may aid in neuronal recovery and, in turn, enhance learning and memory [106, 107]. In the brain’s grey matter, ATP concentration is thought to be controlled by an association between the proteins uMiCK and CK. Besides, only neurons expressing uMiCK have a mitochondrial synthesis of creatine phosphate, indicating that uMiCK protects neurons from energy shortages during increased energy demand. CKBB oxidation has been suggested to explain the decreased ATP production observed in the brains of aged SAMP8 mice [108]. Loss of CKBB activity in aged SAMP8 brains may necessitate an increase in uMiCK expression by injection of LA. Antioxidant defense systems in neurons and synapses would be restored due to this. The increased axonal dystrophy in the nucleus is due to decreased NF-L expression [102, 106]. When α-LA is administered to SAMP8 mice, the NF-L level in their aging brains rises, and the axonal dystrophy appears to be reduced, which improves learning and memory in the SAMP8 mice. An elevated specific carbonyl level of DRP-2 was also found [106], suggesting that oxidative deactivation of DRP-2 is to blame for the decline in learning and memory in older SAMP8. Using α-LA to treat aged SAMP8 mice reduces the oxidative modification of DRP2, possibly restoring DRP-2 activity and thus normal axonal neurogenesis. As a result, α-LA administration improved cognitive function using underlying proteomics mechanisms. More research outlining the proteomic studies should be explored to understand better how lipoic acid improves cognitive function.

Conclusion

As of now, it is not clear how valuable and effective α-LA is in the nervous system; still, antioxidants such as α-LA are known to be beneficial for our health. The antioxidant properties of α-LA and its role in the synthesis of Vit E, C, and GSH make it an attractive therapeutic agent for various diseases, including neurodegenerative disorders, in the future. α-LA has been studied in different studies which involved the treatment of various neural-related diseases. Considering the inflammatory pathways activated in most neural diseases’ pathological processes, α-LA can be regarded as a possibly helpful treatment in neurodegenerative disorders. α-LA and DHLA play a crucial role in biological processes, such as regulating several gene transcriptions and modulating enzymes and chemokines. α-LA is a viable choice for reestablishing mitochondrial function, as it acts as a cofactor for mitochondrial enzymatic complexes—a critical mechanism for energy production and metabolic regulation—as well as directly scavenging ROS in neurodegeneration. α-LA inhibits inflammasomes in neural tissues by decreasing pro-inflammatory mediators such as IL-2, IFN-γ, and TNF-α and raising anti-inflammatory cytokines such as IL-10. α-LA regulates the transcription of nuclear factors Nrf2 and NF-κB in physiological processes. Thus, α-LA is an agent with multiple actions on the neuronal machinery, acting in several mechanisms involved in the pathology of neurodegenerative disorders. Preclinical studies showed that α-LA attenuates neurodegeneration by modulating neuronal apoptotic pathways, supporting a neuroprotective role in Alzheimer’s, Ischemic injury, etc. Clinically, the use of α-LA in different trials highlighted that the administration of α-LA could significantly improve neurodegenerative-related disorders’ symptoms and slow down their deterioration. These characteristics make α-LA a viable supplement for treating neurodegenerative disorders as a therapeutic substitute. Therefore, α-LA can be shown as an effective therapeutic agent for neurodegenerative disorder therapy via different signaling pathways. α-LA appears to be a promising candidate for this type of multi-targeted therapy.