Neuroprotective Role of Agmatine in Neurological Diseases

Abstract

Background:

Neurological diseases have always been one of the leading cause of mobility and mortality world-widely. However, it is still lacking efficient agents. Agmatine, an endogenous polyamine, exerts its diverse biological characteristics and therapeutic potential in varied aspects.

Methods:

This review would focus on the neuroprotective actions of agmatine and its potential mechanisms in the setting of neurological diseases.

Results:

Numerous studies had demonstrated the neuroprotective effect of agmatine in varied types of neurological diseases, including acute attack (stroke and trauma brain injury) and chronic neurodegenerative diseases (Parkinson's disease, Alz-heimer’s disease). The potential mechanism of agmatine induced neuroprotection includes anti-oxidation, anti-apoptosis, anti-inflammation, brain blood barrier (BBB) protection and brain edema prevention.

Conclusions:

The safety and low incidence of adverse effects indicate the vast potential therapeutic value of agmatine in the treatment of neurological diseases. However, most of the available studies relate to the agmatine are conducted in experi-mental models, more clinical trials are needed before the agmatine could be extensively clinically used

1. Introduction

Neurological diseases have always been one of the leading causes of mobility and mortality worldwide. It can be divided into two typical classes: acute attack (stroke, trauma brain injury et al.) and chronic neurodegenerative diseases (Parkinson's disease, Alzheimer’s disease, Huntington's disease et al.) [1].

The pathological mechanism in the process of neurological diseases and neuroprotective effects of various drugs have been comprehensively studied throughout these years, which consist of cellular apoptosis, inflammation, oxidative stress, brain edema and so on [2, 3]. Agmatine, a polyamine exerting its effects in cellular apoptosis, inflammation, oxidative stress and brain edema, has been demonstrated to be neuroprotective in many neurological diseases [4, 5] (Fig. 1).

Fig. (1).

Overview of the neuroprotective effects of agmatine.

Agmatine has been discovered for over 100 years. Nobel Laureate Albrecht Kossel first reported it in 1910 [6], and he found that it was ubiquitously synthesized in the bacteria and plants [4, 7]. It was formed by decarboxylation of L-arginine generating from arginine decarboxylase, and hydrolyzed to putrescine and urea by agmatine [8, 9]. The chemical structure of agmatine was displayed in Fig. (2).

Fig. (2).

Chemical structure of agmatine (Tayfun I. Uzbay et al., 2012.).

However, the research of Agmatine reached little progress during the 20th century due to lack of understanding of the enzyme arginine decarboxylase (ADC), which could synthesize agmatine from arginine [7]. The breakthrough was not made until 1994 that agmatine and ADC were finally found in the mammalian brain by Reis and colleagues [10]. Ensuing numerous studies focused on the physiological and pharmacological effects of agmatine on mammals. It was reported that agmatine displays protection in many organ diseases, including cardio-protection, nephro-protection, gastro-protection, neuro-protection and gluco-protection [11]. For example, agmatine had been reported to reduce heart rate and blood pressure by activating central and peripheral control systems through the regulation of imidazoline receptors subtypes, norepinephrine release and NO production [12], and could also improve the hemodynamic recovery of cardiac ischemia or restore blood pressure [13]. In an experimental research, Lortie, M.J. et al. found that agmatine can improve the glomerular filtration rate (GFR) by induction of endothelial NO synthase (eNOS) [14]. Referring to the cytoprotective mechanisms, agmatine was believed to attenuate renal disease [15].

In the past decades, numerous studies have explored the potential mechanisms of neurological diseases and neuroprotective effects of various drugs. But the adverse effects of some drugs posed great limitation to further clinical trials. Interestingly, agmatine was found to ubiquitously exist naturally in plants, animals, and some other foodstuff. The sulfate salt containing agmatine had been used as a dietary ingredient many years ago and now is available as a nutraceutical [16]. Gilad and his colleagues assessed long-term safety of oral agmatine treatment by consuming a daily high dosage of oral agmatine over a period of 4-5 years. All measurements remained within normal values and no discomfort was observed during the follow-up period [17]. Moreover, the neuroprotective effect of agmatine has been demonstrated by extensive studies since 1994. The low incidence of adverse effects and vast therapeutic value has earned great attention.

In 1995, Gilad, et al. firstly reported the neuroprotective action of agmatine [18]. Henceforward, more and more studies showed neuroprotection of agmatine in stroke, traumatic brain injuries, neurodegenerative disorders, neuropathic pain, epilepsy, and even in mental disorders. Anti-oxidation, anti-apoptosis, anti-inflammation, brain blood barrier (BBB) protection and brain edema prevention are the common mechanisms involved in the neuroprotective effects. This review would focus on the neuroprotective actions of agmatine and its potential mechanisms in the setting of neurological diseases.

2. The neuroprotective effects of agmatine in neurological diseases

2.1. The Effect of Agmatine in Ischemic Stroke

Stroke has been the second most common disease to cause death and disability in adults around the world [19]. Ischemic stroke, which accounts for about 87% of cases, is the most common subtype of stroke [20]. Ischemic stroke is the result of insufficient blood and oxygen supply to the brain. The cell in central portion of the ischemic tissue, known as infarct core, is afflicted with irreversible damage and the area around the infarct core, called penumbra, is at risk of infarction and can be reverted [21].

Previous studies have proved that the occurrence of stroke promoted the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which could destroy the structure of BBB, leading to brain edema [22]. In addition, the disruption of neuro-inflammatory or oxidative stress balance could produce excessive inflammatory cytokines, reactive oxygen species (ROS) and free radicals, which initiate cell death ultimately [23, 24].

Numerous experimental researches, most of which focused on the salvation of the tissue in the penumbra, had been carried out to explore the optimal neuroprotective drugs for cerebral ischemia [25, 26]. But the severe side-effects of these drugs posed great limitation on further clinical trials. In contrast, agmatine displayed its safety in both experimental and clinical trials. The sulfate salt of agmatine had been used as a dietary ingredient many years ago and now is available as a nutraceutical [16, 27]. Besides, many studies confirmed the neuroprotective role of agmatine in strokes [28].

Kim et al. [4] showed the neuroprotective effects of agmatine both in vivo and in vitro through the mechanism of reducing the production of nitric oxide (NO) by competitively inhibiting nNOS and iNOS. Meanwhile, agmatine can also activate eNOS (nitric oxide synthase) in endothelial cells, and thus increase the production of NO, which acts as a vasodilator to increase the blood flow in the ischemic areas [29, 30]. Feng et al. [31] reported that both endogenous and exogenous agmatine can exert their functions on the NOS and reduce hypoxic-ischemic brain injury in neonatal rats. Besides, many other studies verified the effects of agmatine on the three kinds of NOS mentioned above in the setting of cerebral ischemia [11].

Brain blood barrier (BBB) is extremely important in maintaining homeostasis and microvascular integrity [5]. However, the cerebral ischemic attack could induce upregulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which could destroy the integrity of BBB. Hyun et al. and Yang et al. both demonstrated that exogenous agmatine could inhibit the expression of MMP-2 and MMP-9 by induction of eNOS in vitro [32, 33]. Moreover, Hyun and his colleagues utilized retrovirus to induce the endogenous agmatine, and their findings suggested that endogenous agmatine could reduce the MMP-2 and MMP-9 expression by regulation of eNOS, NO and activation of transcription factor 3(ATF3) [33]. In addition to detecting MMP-2 and MMP-9, Ahn and his colleagues took advantage of dynamic contrast-enhanced MR imaging to evaluate the beneficial effects of agmatine on BBB stabilization [34].

Brain edema frequently was observed to be involved in the worsening process of cerebral ischemia and contributed to increasing mortality after attack of stroke. Jae and his colleagues explored the mechanism of brain edema and the effects of agmatine. Their findings suggested that the BBB disruption and the upregulation of aquaporins-1 and -9 (AQPs) were well correlated with brain edema, and these disadvantages can be significantly attenuated by agmatine treatment [35]. Besides, some other studies revealed the effects of agmatine on reducing the expression of AQP-4 and thus attenuated the brain edema as well [36-38].

Additionally, studies also showed that agmatine contributed to reducing the apoptosis of neuron and cerebral astrogliosis after cerebral ischemia in a rat model [36]. Jeong et al. found anti-inflammatory character of agmatine in diabetic middle cerebral artery obstruction (MCAO) rats by decreasing the expression of high-mobility group box 1, RAGE, toll-like receptor(TLR)-2,4 [38].

Overall, the agmatine exerted its neuroprotective effect on ischemic stroke both in in vivo and in vitro experimental models.

2.2. The Effect of Agmatine in Traumatic Brain Injury

Traumatic brain injury (TBI) is a condition of emergency and ranks second to conventional stroke in causing death and disability, which place tremendous burden on the family and society [39]. It can be divided into primary injury and secondary injury [40]. A series of pathophysiological changes are involved in the progress of TBI, which include brain edema, cellular apoptosis, BBB disruption, inflammation and so on [41-43]. However, there were no ideal therapeutic drugs for the patients suffering from TBI so far. Recently, many studies verified the beneficial effects of agmatine in TBI. In 1996, Gad and his colleagues explored the neuroprotective effects of agmatine in rodent brain injury [44]. Previous researches reported that excessive accumulation of glutamate or NO could lead to cellular ischemia and neurotoxicity [29, 45, 46]. In a rat model of fluid percussion brain injury, Jinn et al. found that agmatine could reduce excessive glutamate and NO, and attenuated TBI resultantly. Furthermore, they also demonstrated that FPI-induced intracranial hypertension, cerebral hypotension, cerebral infarction, motor and proprioception deficits and body weight loss could all be alleviated by agmatine [47]. In 2010, Jinn and his colleagues conducted a series of experiments on the neuroprotective effects of agmatine, and found that agmatine could improve the outcome of TBI in rats by attenuating neuronal and glial apoptosis, inhibiting gliosis, promoting angiogenesis and neurogenesis [48]. In addition, Jae and his colleagues found that agmatine could reduce brain edema by suppressing the expression of AQP1, 4 and 9. Besides, they also found that agmatine could inhibit cellular apoptosis by inhibiting the phosphorylation of MAPKs and increasing the nuclear translocation of NF-κB after TBI [49]. In addition, agmatine had also been proved to play neuroprotective role in rat spinal cord model. It could significantly restore the locomotor function and reduce tissue damage by blocking the NMDA receptor and NOS [50].

2.3. The Effect of Agmatine in Neurodegenerative Diseases

2.3.1. Effects of Agmatine in Parkinson’s Disease

Parkinson’s disease (PD), commonly presented as motor dysfunction, is one of the most common neurodegenerative diseases in the aged [51]. It was reported that the degeneration of dopaminergic neurons in the substantia nigra pars, which leads to motor dysfunction, is the on-off step in the progression of PD. Recently, many studies showed that glutamatergic neurotransmission also contributed greatly to the pathogenesis of PD [4, 52, 53].

Excitatory amino acids were assumed to have neurotoxicity and aggravate the condition of patients with PD [4]. NMDA is the receptor of excitatory amino acid, and its antagonists like memantine, amantadine and agmatine were extensively proved to ameliorate motor function of PD patients [5, 54, 55].

In the experimental model of PD induced by rotenone, agmatine could significantly decrease the level of oxidative stress in SH-SY5Y cells. Besides, agmatine could also reduce the cellular apoptosis induced by rotenone [56]. In addition, a recent in vitro study demonstrated that agmatine could prevent redox reaction and cellular injury [57].

Gilad and his colleagues developed a new mouse PD model by intranasal administration of 1-methyl-4-phenyl-4-1,2,3,6-tetrahydropyridine (MPTP), and found that agmatine could provide a partial (31%) protection of PD induced by MPTP [5]. Matheus and his colleagues delivered agmatine to a group of aged mice before the treatment with MPTP. Their results demonstrated that agmatine could prevent the occurrence of motor, cognitive and neurological impairments induced by MPTP [58].

2.3.2. Effects of Agmatine in Alzheimer’s Disease

Alzheimer’s disease (AD), commonly accompanied with progressive cognitive dysfunction, is also one of the most common neurodegenerative diseases in the aged. Its pathological hallmarks are extracellular deposition of amyloid-beta peptide, and presence of neurofibrillary tangles in the neuron [59] which are mainly distributed in the hippocampus, cerebral cortex and basal ganglia [60, 61]. Currently, the accumulation of amyloid-beta peptide, abnormal phosphorylation of Tau peptide, oxidative stress and radical injury has been recognized as the main pathophysiologic mechanism of AD [62, 63]. Agmatine showed its neuroprotective role in oxidative stress, radical injury and other pathological process. For example, Baranov et al. revealed that agmatine could exert its anti-oxidative effect by activating many kinds of antioxidants including glutathione [64]. Besides, agmatine could decrease the level of free radical and inhibit the accumulation of amyloid-beta peptide [65].

N-methyl-D-aspartate (NMDA) is the receptor of the excitatory amino acid and its dysfunction can lead to the apoptosis of neuron [4]. It was reported that the level of endogenous agmatine rose sharply on the setting of brain injury [47], and exerted its neuroprotective effect by competitively inhibiting the NMDA receptor and activity of excitatory amino acid [24]. In the AD patients, accumulation of amyloid-beta peptide in neuron increased the level of excitatory amino acid, which then produced neurotoxicity. Agmatine was reported to postpone apoptosis of neuron by inhibiting the neurotoxicity of excitatory amino acids [66]. Except for its effect on neurotoxicity, amyloid-beta peptide could also down-regulate the insulin receptor which widely exists in the central nervous system. However, retaining the insulin receptor and its ligand is quite important in the treatment of AD [67, 68]. Somang and his colleagues demonstrated that agmatine could promote the secretion of insulin and protect the insulin receptor via binding with the imidazoline receptors [67]. This process could then reduce the accumulation of amyloid-beta peptide and inhibit the abnormal phosphorylation of Tau peptide, which ultimately ameliorate the cognition and memory injury of AD patients [69].

2.4. The Effect of Agmatine in other Neurological Diseases

2.4.1. Effects of Agmatine in Epilepsy

Epilepsy is a chronic process characterized by recurrent paroxysmal seizures [70]. Epileptogenesis resulted from synchronization and propagation of excessive excitability, which spread from hyper-excitable neurons and glial cells to the normal non-epileptogenic tissue [71, 72]. The glutamatergic receptors and NMDA receptor were reported to be involved in the initiation of some kinds of epilepsies [73-75]. Besides, epileptic seizures could increase the production of NO, and pre-treatment with NOS inhibitors could give precaution against some types of seizure [76, 77]. As aforementioned, the agmatine could act as an antagonist of NAMD receptor, thus several studies had been carried out to test the neuroprotective effects of agmatine in experiment animals with epilepsies. Their results demonstrated that agmatine could reduce both the incidence and intensity of epilepsy and also exert anticonvulsant effect [78]. Additionally, agmatine could inhibit the activation of NOS and reduce the production of NO. It was reported that both the NOS inhibitor and exogenous agmatine had neuroprotective effects on epilepsy [79, 80]. Except for the anticonvulsant effect, agmatine could also strengthen the anticonvulsant effect of some other drugs, such as phenobarbital, valproate and lithium chloride [81, 82]. Overall, agmatine proved to have neuroprotective effects in epileptic patients.

In the meanwhile, several other studies [83, 84] contradicted this inference, Abe et al. reported that agmatine (200-800μM) could induce the release of glutamate, which could lead to neuronal death. Besides, Luszczki and his colleagues also suggested that the synergistic effect of agmatine in anticonvulsant is also uncertain, which meant that further researches of agmatine in epilepsy are needed before it can be extensively clinically used.

2.4.2. Effects of Agmatine in Mental Disorders

Mental disorder is a group of systemic diseases characterized by a variety of physical and mental discomfort, such as depression, anxiety, addiction, schizophrenia and so on [85]. Agmatine has been long-term studied for its neuroprotective effects in mentor diseases. Many studies reported that agmatine exerts its antidepressant-like action by inhibiting the NMDA receptors or interacting with 5-HT1A/1B and 5-HT2 receptors [86-88]. Besides, agmatine could suppress the expression of NOS, NMDA receptors or imidazoline receptors, and alleviate drug addiction induced by opioid, morphine, ethanol or psychostimulants [89, 90]. Additionally, agmatine may have beneficial effects on anxiety, schizophrenia and some other mentor diseases in experimental model [91, 92].

4. Neuroprotective Properties of agmatine in Neurological Diseases

The neuroprotective effects of agmatine have been widely studied in various neurological diseases and the mechanism involved in this effect includes anti-oxidation, anti-inflammation, anti-apoptosis, BBB protection and brain edema prevention. The following review will particularly probe into these molecular mechanisms.

4.1. Anti-apoptotic Effects of Agmatine

Apoptosis is one type of cell death characterized by energy dependence and programmed cell death [93]. The term ‘apoptosis’ was first described by Kerry et al. [94]. Apoptosis is of vital importance to normal physiological metabolism, growth and development, keeping hemostasis by scavenging the aging or damaged cells, shaping of organs or regulating immune system by removal of defective and excessive cells [95, 96]. However, uncontrolled apoptosis may result in various pathological processes of different diseases, like cancers, Alzheimer’s disease and stroke [97, 98]. El-Sherbeeny et al. demonstrated that agmatine could protect rat liver from nicotine-induced damage by inhibiting the production of proapoptotic protein Bax [99]. In vitro, Mary and his colleagues identified the anti-apoptotic effects of agmatine to the Ha-Ras-transformed murine NIH-3T3 cell line by reducing the expression of Bax and caspase-3 [100]. In addition, agmatine was also observed to be involved in the modulation of programmed cell death in rats and inhibit the proliferation of human mast cell leukemia cells (HMC-1) and HL-60 cells [101, 102]. Many researches have demonstrated the anti-apoptotic effect of agmatine in various neurological disorders. For example, Kim and his colleagues demonstrated that agmatine could reduce cellular apoptosis in traumatic brain injury of rats by inhibiting phosphorylation of MAPKs and increasing nuclear translocation of NF-kappaB [51]. In addition, Zarifkar reported that inhibition of caspase-3 expression by agmatine could also prevent hippocampal apoptosis and spatial memory impairment induced by lipopolysaccharide (LPS) [103]. Besides, in rat model of Alzheimer’s disease, agmatine reduced cellular apoptosis through inhibiting the expression of caspase-3 and Bax, and improved the level of Bcl2, PI3K, Nrf2, and gamma-glutamyl cysteine [69].

Several in vitro studies reported the protection of agmatine on the human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). Agmatine exerted its anti-apoptotic effects by increasing the amount of phosphorylated Akt /Akt, inhibiting the GSK-3β activity and decreasing the expression of apoptotic markers, such as caspase 3, Bax and cytochrome c.

Overall, the anti-apoptotic effect of agmatine had been well demonstrated in neurological diseases.

4.2. Anti-inflammatory Effects

Inflammation is a complex immune response of organisms to the injury. Under normal conditions, inflammation could help to scavenge the necrotic cells or tissues, and initiate the tissue repair process [104]. However, excessive activation of immune responses is harmful to the organisms and can cause injury [105]. Agmatine exerted its anti-inflammatory effect in many ways. For example, in vivo, Taksande demonstrated that agmatine could attenuate the symptom of arthritis by reducing the level of inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukins (IL)-6 [106]. Meanwhile, an in vitro study showed that agmatine could inhibit the production of pro-inflammatory cytokines, such as IL-6, TNF-α and CCL2, and reduce the cell death [107].

Inflammatory neurodegeneration also plays a key role in the pathogenesis of neurological diseases, including acute diseases (stroke or traumatic injury) and chronic neurodegenerative diseases (AD, PD, or HD) [105]. Sahin showed that agmatine could attenuate sub-chronic stress by down-regulating the gene expression of nod-like receptor protein 3 (NLRP3) inflammasome components (NLRP3, NF-kappaB, PYCARD, caspase-1, IL-1β and IL-18) and reducing the level of pro-inflammatory cytokines. Besides, agmatine could also revert the change of anti-inflammatory cytokines, such as IL-4 and IL-10 [108]. In addition, the anti-inflammatory effect of agmatine was also proved in many other neurological diseases, such as transient brain ischemia, depression, TBI and micro-opioid receptor tolerance, by regulating the expression of inflammatory cytokines [22, 109].

4.3. Anti-oxidant Effects

Oxidative stress, which is mainly caused by overbalance of pro-oxidant/anti-oxidant system in cells, takes part in the pathogenesis of many diseases [110-112]. Various agents including agmatine had been demonstrated to decrease oxidative stress and protect organisms from injury. Iizuka reported that agmatine could protect the retinal ganglion cells (RGCs) from H2O2-induced injury through the alpha 2-adrenergic receptor signaling pathway [113]. Bratislav found that agmatine could exert its anti-oxidative effect by protecting antioxidant defense system and restoring the antioxidant capacity in liver tissue [114]. Besides, several studies had demonstrated the anti-oxidative effect of agmatine in the setting of neurological diseases. Gawali and his colleagues reported that agmatine could ameliorate depressive-like behavior by reducing the oxidative/nitrosative stress evoked by LPS in hippocampus and prefrontal cortex [115], and this effect may be achieved via preventing lipid peroxidation and regulating the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) [116]. In addition, agmatine has also been proved to exert anti-oxidative stress in stroke and TBI by reducing the generation of reactive oxygen species (ROS) and free radicals [11].

4.4. BBB Protection and Brain Edema Prevention

BBB is a continuous, non-fenestrated system which regulates the movement of many particles and cells, such as ion, toxicant and inflammatory cells. Any factors disrupting the BBB would deteriorate the condition of neurological diseases, including stoke, TBI and neurodegenerative diseases [117, 118]. The most common complication of BBB disturbance was the vasogenic brain edema, which was reported to be related to the early expression of matrix metalloproteinases-2,9 after brain injury [119, 120]. Agmatine was reported to have significant effect in inhibiting the expression of matrix metalloproteinases [33]. Therefore, regulation of agmatine on the expression of matrix metalloproteinases may be the potential mechanism of BBB protection and vasogenic brain edema attenuation.

In addition, another type of brain edema that commonly occurs during brain injury is cytotoxic brain edema. One of the most frequent and elaborated mechanisms of cytotoxic edema is the dysfunction of AQP in the brain. The AQP are a group of water channel proteins which regulate the movement of water molecule between plasma membrane. AQP1, 4 and 9 were clearly identified in the brain tissue. AQP1, 4 were reported to be involved in cerebrospinal fluid formation and their dysfunction could also contribute to brain edema [121, 122]. Several studies demonstrated that the mechanism of agmatine in preventing cytotoxic edema is to suppress the expression of aquaporin (AQP)-1, 4, and 9. The changes had been demonstrated in many types of neurological diseases, such as TBI, stroke or degenerative diseases [8, 36, 51].

Although the effect of agmatine in reducing the brain edema had been well demonstrated, its therapeutic effect was doubted by some researchers and more studies should be launched [4, 36, 45].

Conclusion and Perspective

Overall, agmatine exerted its neuroprotective effects in various neurological diseases, including acute attack (brain ischemia and trauma brain injury) and chronic neurodegenerative diseases (Parkinson's disease, Alzheimer’s disease). The underlying mechanism involved anti-oxidation, anti-apoptosis, anti-inflammation, brain blood barrier (BBB) protection and brain edema prevention. The safety and low incidence of adverse effects indicate the vast potential therapeutic value of agmatine in the treatment of neurological diseases. However, there are still some drawbacks in the research of agmatine. On one hand, minimal studies involved the neuroprotective effect of agmatine reported in some areas, such as brain hemorrhage, or Huntington's disease. In addition, the administration of agmatine was limited in crossing the BBB and its rapid elimination by the kidneys affecting its pharmacological efficacy. Besides, most of the available studies relating to agmatine are conducted in experimental models. More clinical trials are however needed before agmatine could be extensively clinically used.

LIST OF ABBREVIATIONS

AD

Alzheimer’s disease

ADC

Arginine decarboxylase

AQPs

Aquaporins

ATF3

Transcription factor 3

BBB

Brain blood barrier

eNOS

Endothelial NO synthase

GFR

Glomerular filtration rate

GPx

Glutathione peroxidase

GR

Glutathione reductase

HMC-1

Human mast cell leukemia cells

IL

interleukins

MCAO

Middle cerebral artery obstruction

MMP-2

Matrix metalloproteinase-2

MMP-9

Matrix metalloproteinase-9

MPTP

1-methyl-4-phenyl-4-1,2,3,6-tetrahydro-pyridine

NMDA

N-methyl-D-aspartate

NO

Nitric oxide

PD

Parkinson’s disease

RGCs

Retinal ganglion cells

ROS

Reactive oxygen species

SOD

Superoxide dismutase

TBI

Traumatic brain injury

TLR

Toll-like receptor

TNF

Tumor necrosis factor

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no conflict of interest, financial or otherwise.