Targeting S100B Protein As A Surrogate Biomarker And Its Role in Various Neurological Disorders Part 3

5. S100B IN PARKINSON'S DISEASE

Parkinson's disease (PD) is a prevalent progressive neurodegenerative disorder that is described by aggregation of α-synuclein in cortical or brain stem region [68]. 

Parkinson's disease is a neurological disease caused by the death of nerve cells, and its main symptoms are limb stiffness, tremors, and decreased coordination. Although most people think that Parkinson's disease is just a disease that affects physical activities it can also have a great impact on patients' memory.

Studies have shown that Parkinson's patients will suffer from cognitive function and memory. Especially when performing complex cognitive tasks, Parkinson's patients will experience severe memory decline, which may have a great impact on their lives.

However, Parkinson's patients do not have to worry too much. Although there are some memory difficulties, there are many ways for them to relax their physical and mental fatigue and effectively improve their memory by improving their lifestyle.

First, enhancing mental health by maintaining a positive attitude towards life, participating in training, and having an active social life, while doing proper exercise and physical activities such as massage, can help reduce the negative effects of anxiety and fatigue.

Secondly, using note-taking tools such as calendars and reminder applications to help patients better organize their time can help improve memory and work efficiency.

Finally, meaningful memory training can also effectively improve memory. Parkinson's patients can strengthen their memory through methods such as games, reading, and retelling stories.

In conclusion, although the memory of Parkinson's patients may be affected to a certain extent, they can effectively improve their memory by improving their lifestyle and actively training mental and physical activities. It is important to maintain a positive attitude, improve self-confidence, and believe that you can overcome any difficulties. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in many ways.

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The first and most prominent physical disabilities due to these variations include motor incoordination which is collectively called Parkinsonism. These include insufficiency and slow movement that is akinesia, bradykinesia, rigidity, and tremors produced at rest [69]. 

Pathogenesis of PD focuses on ROS, the initiation of oxidative stress that results in oxidative damage to substantia nigra pars compacta. Free radical species being the cause of the death of a dopaminergic cell in PD is unclear, but some data have suggested that hydroxyl radical (OH'), NO, and peroxynitrite are involved [70]. 

Nitric oxide synthase (NOS) activation produces NO, which reacts with superoxide to form peroxynitrite. This molecule modifies nucleic acid, protein, and lipid, in an oxidative manner, resulting in nuclear damage, proteasome inhibition, mitochondrial damage, and endoplasmic reticulum stress (ER). 

Excessive level of nitrosative stress leads to the hyperactivation of glutamate receptor group N-methyl-D-aspartate (NMDA), mitochondrial dysfunction, and cell aging. Excessive free radicals and NO species were reported to activate the pathological mechanism including abnormal mitochondrial dynamics, misfolded proteins, and apoptotic pathways in dopaminergic cells [71]. 

Some studies have suggested that excessive production of NO may contribute to these pathological processes, mainly by S-nitrosylation of specific target proteins, such as ubiquitin-protein ligase, parkin, protein disulfide isomerases (PDI), and mitochondrial degradation by ß-amyloid-related S-nitrosylation of dynamin-related protein-1. 

PDI is responsible for the normal folding of proteins in the ER, among these proteins [72]. In addition, No mediated effects on dopaminergic neuron cells can include the inhibition of mitochondria complexes I, II, and IV, cytochrome oxidase, ribonucleotide reductase, glyceraldehyde-3-phosphate dehydrogenase, superoxide dismutase, lipid peroxidation, activation or initiation of DNA strand breakage, protein oxidation and increased production of toxic free radicals including hydroxyl radicals and peroxynitrite. 

Evidence has suggested that excessive RNS/ROS may lead to UPS impairment and misfolding of protein molecules, resulting in aggregation of protein and dopaminergic neuronal death [73]-the low expression of S100B protein results in neuroprotection due to decreased microgliosis, AGEs, and TNF-alpha expression. 

There are increased indications that S100B is not only involved in inflammation but also neurodegenerative disease activates proinflammatory cytokine release and leads to damage to dopaminergic neurons. The increased level of S100B proteins in post-mortem substantia nigra of PD patients has been reported as compared with the normal tissue group in the CSF [74]. 

Furthermore, S100B shows dual action at low concentration (nanomolar), activates neurotrophic factor, and promotes neuronal survival as well as the growth of neurites during the development phase [75]. 

It also initiates neuronal apoptosis at micromolar concentrations both by direct action on neurons and microglia activation [76]. To some range, these effects may be mediated by an iNOS enzyme which increases nitric oxide production, intracellular calcium levels, and activation of caspase-3 [24]. Further, it has been reported that the treatment of astrocyte culture with S100B protein leads to iNOS activation and nitric oxide production. 

Nitric oxide produced in response to S100B can cause astrocytes to undergo apoptotic cell death. Nitric oxide-mediated excitotoxicity, inflammation, oxidative stress, mitochondrial function impairment, DNA damage, and S-nitrosylation of various proteins lead finally to neuronal death [47] (Fig. 3). 

This indicates that S100B could be a promising marker for the degree of disease severity during the beginning of the disease. PD patients have lower levels of S100B and individuals with reduced S100B levels could be more vulnerable to neurological problems. 

These findings suggest that S100B may have a possible role in either the underlying PD development mechanism or in the assessment of disease [14] Furthermore, astroglial C6 and oligodendroglial OLN-93 cells treatment with haloperidol and clozapine at a concentration corresponding to the therapeutic dose range of these drugs decreases the S100B release in vitro [77].

6. S100B IN MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is an autoimmune disease of CNS caused by chronic inflammatory demyelination of neurons, affecting young people [78]. In early disease stages, it is characterized by the T-cell activation, infiltration, and accumulation of monocyte macrophages that promote damage to the myelin sheath which further leads to the formation of focal demyelinated lesions [79]. 

Moreover, a higher S100B level triggers the activation of astrocytes and microglial promoting the NO release [80]. NO is a free radical that is found at a higher concentration than the normal in inflammatory lesions of MS. This increased concentration occurs because of the appearance of iNOS in astrocytes and macrophages. 

Markers of NO production such as nitrite and nitrate concentrations are increased in the blood, CSF, and urine of MS patients. Also, evidence suggests the function of NO in various disease features such as BBB damage, injury of oligodendrocyte, demyelination, and degeneration of axon and it further contributes to functional loss due to axonal conduction impairment [81]. 

Elevated S100B level was first detected in the cerebrospinal fluid of acute-phase MS patients [82]. In the diagnosis of relapsing-remitting MS patients, elevated levels of S100B in the CSF or serum were detected, which decreased after therapy with immunosuppressive or natalizumab [83]. During the injury, an increased level of S100B may induce glial reactivity, aggravating tissue damage or delaying remyelination. Increased S100B levels were detected in the CSF of relapsing-remitting MS patients after diagnosis [84]. 

Active demyelinating MS lesions showed an elevated level of S100B and its receptor, RAGE in the lesion area while chronic active lesions showed raised S100B levels in demyelinated areas with lower expression of RAGE receptors in the rim [85]. Interestingly, reactive astrocytes were recognized as the prevailing S100B cellular source, although activated microglia or macrophages express RAGE. 

A study on the expression of RAGE and S100B in MS lesions reveals that active demyelinating lesions in MS are characterized by myelin loss and increased levels of proteolipid protein-positive macrophages (PLP). In white matter regions, S100B expression was markedly increased and localized to cell bodies and reactive astrocytes-like cell processes. 

The expression of RAGE was also markedly raised in active white matter lesions and localized to macrophages and activated microglia, which was also confirmed by the use of double immunofluorescence labeling. Demyelinated lesion centers devoid of immune cells and activated microglia and macrophage rims are used to characterize the analysis of chronically activated MS lesions [87]. 

The expression of S100B was raised throughout the demyelinated areas. S100B is elevated in CSF, serum, and post-mortem plaques of MS patients being related to demyelination and glial reactivity. Barros et al. showed that neutralization of S100B has a beneficial effect in an ex vivo demyelinating model by targeting S100B with pentamidine that could prevent MS-related pathogenesis in the ex vivo model. 

Pentamidine not only prevents demyelination and axonal impairment but it also exacerbates the production of inflammatory factors (TNF-α, IL-1β, HMGB1). Also in the in vivo animal model of MS, the Experimental Autoimmune Encephalomyelitis, it was evaluated if pentamidine could prevent MS disease course [88]. 

EAE-induced animals given pentamidine reached a lower disease clinical score and provided fast recovery. Results show that S100B is involved in MS pathology and its inhibition may be a new possible therapy to decrease damage and improve disease recovery [79].

7. S100B IN TRAUMATIC BRAIN INJURY

TBI is a type of acquired brain injury from the external mechanical force that probably leads to permanent or temporary cognitive, physical, and psychological function impairment with or without loss of consciousness [89]. 

Pathologically, as found in brain injuries after acute ischemia followed by reperfusion, a decrease in the availability of oxygen disturbs the brain's energy balance and raises ROS levels. Highly reactive chemicals such as ROS (NO, superoxide anion, and hydroxyl radicals) attack and damage DNA [90]. It has been reported that NO levels were raised with TBI demonstrating modulation of increased NO homeostasis. 

There is increasing evidence from experimental and clinical data that an inappropriate inflammatory response plays a major role in the pathology of TBI. Changes in levels of NO have also been linked with different forms of trauma including secondary damage after TBI [88]. Various studies have shown the upregulation of NO synthase enzymes, contributing to rises in the levels of NO in the brain, which leads to TBI-associated glutamate cytotoxicity including mitochondrial dysfunction pathogenesis. 

TBI is associated with elevated rates of NO in isolated organs, suggesting that TBI can cause systemic changes in NO regulation that can be beneficial or harmful [91]. Extracellularly administered S100B within normal and TBI states stimulates neurogenesis and neuronal plasticity as well as improves neuro-modulating functions involved in learning and memory [52]. 

S100B performs a dual function that at low concentration,t is beneficial and at higher concentration, the effects are harmful [92, 93]. Rapidly increasing extracellular levels of S100B have been shown to result in cell death and neuronal dysfunction because of an inflammatory response that activates astrocytes, and microglia along with extracellular elevation in calcium level and nitric oxide levels [94, 95]. 

The BBB of the patient suffering from TBI gets disrupted causing the leakage of proteins from CSF following cerebral deterioration and the formation of edema [96]. The albumin ratio between CSF: and serum (QA ) is sometimes used to detect the degree of disruption of BBB [97]. Some authors claim that through the disrupted BBB, S100B is released into the serum. The concentration of S100B in the CSF could be up to 100 times higher than in serum [98].

8. S100B IN SCHIZOPHRENIA

Schizophrenia is a severe mental illness with a variety of symptoms that affect cognitive function, perceptual experiences, speaking, and other behavioral activities. Schizophrenia has become a severe public health problem and exerts enormous economic and personal burdens worldwide [99]. Astrocyte and oligodendroglial cells mediated increased S100B release may lead to neuroinflammatory processes by the activation of microglial expression of COX-2 and iNOS causing dysfunction of neurons and apoptosis [100]. 

NO is an important NMDA receptor activating the second messenger, which interacts with pathways of dopamine and serotonin, and the abnormal activity associated with these pathways is suggested to be implicated in schizophrenia pathophysiology [101]. NO also performs the uptake, storage, and release of neurotransmitters and mediators such as acetylcholine, GABA, glutamate, noradrenaline, glycine, and taurine. 

Furthermore, NO gets diffused across the cell membranes to activate their receptors extrasynaptically. Studies expose the significant disturbed levels of NO in the structures of the brain such as the hypothalamus, striatum hippocampus, cerebellum, and fluids of schizophrenic patients. These changes may lead to neurodevelopment alterations related to schizophrenia [102]. 

S100B has been proposed as a marker of astrocyte activation and brain dysfunction. Preclinical studies and clinical reports of schizophrenia and concentration of S100B are very consistent. Schizophrenia patients have higher S100B concentrations than healthy controls [103]. Green et al. studied the increased concentration of S100B proteins in the CSF of schizophrenia patients that could be related to an increased permeability of BBB in disease state [104]. 

Similarly, increased expression of S100B has been detected in cortical astrocytes of paranoid schizophrenia cases, while decreased oligodendrocytic expression has been observed in residual schizophrenia. S100B may act as a cytokine after secretion from glial cells, CD8+ lymphocytes, and NK cells, activating monocytes and microglial cells. 

Moreover, S100B exhibits adipokine-like properties and may be dysregulated in schizophrenia due to disturbances in insulin signaling, leading to the increased release of S100B and free fatty acids from adipose tissue [105]. S100B is highly expressed in astrocytes and to a lesser extent in certain neuronal populations such as oligodendrocytes and adipocytes. Elevated serum level of S100B in schizophrenia is correlated with insulin resistance. Increased glucose and C-peptide levels were observed in the schizophrenia cohort, and C- C-peptide/ glucose ratios predicted S100B levels [105].

9. S100B IN EPILEPSY

current and spontaneous seizures caused by excessive, abnormal, and hypersynchronous neuronal discharge [106]. An imbalance between the excitatory glutamatergic and inhibitory GABAergic neuronal discharges causes brain damage and cell loss [107]. Astrocytes, a subtype of glial cells, play an important role in regulating cerebral ion homeostasis, transmitter regulation, maintenance of the blood-brain barrier (BBB), and structural, as well as metabolic support of neuronal cells. 

Recent evidence has indicated that the blood-brain barrier (BBB) dysfunction contributes to an etiological factor of seizures [108]. Alteration of BBB permeability is associated with seizure activity. In addition, it was demonstrated that BBB permeability can be assessed by measuring the serum level of the protein S100B released by astrocytes [109]. Several studies have revealed that the increase in the level of S100B in the CSF and temporal lobe of epileptic patients may be the result of the elevated production or release by the dysfunctional astrocytes. 

A higher level of S100B can also elevate NO expression and induce the death of astrocyte cells [110]. NO causes the loss of neurons and leads to reactive glial cell proliferation, thus potentially participating in epilepsy pathogenesis. There are earlier studies that report the NO inhibition to prevent convulsions [111]. Epilepsy animal models and post-surgery brain specimens from epilepsy patients have also indicated increased levels of S100B in brain tissue [112]. Available reports on S100B demonstrated different S100B levels in epilepsy. 

Portela et al., in 2003, reported the normal level of serum S100B protein in focal epilepsy patients, and Lu et al., in 2010, reported increased levels of plasma S-100B in patients with MTLE as compared with the normal patient [113, 114]. Tergau et al. reported high levels of CSF S100B in temporal lobe epilepsy patients compared to controls [108]. In the study by Lu et al., the S-100B protein concentration was shown to correspond with the epilepsy severity, and hippocampal sclerosis patients had higher levels of plasma S100B than those with MTLE without hippocampal sclerosis [115]. 

An increased serum concentration of S100B may be a characteristic of neuronal damage in an epileptic brain [116]. Increased S100B serum levels have been observed in children with temporal lobe epilepsy. Atici et al. reported that levels of S100B protein were normal following a seizure in patients with simple febrile convulsions [117]. 

Furthermore, recently, Calik et al. demonstrated similar results from a study examining the serum and CSF levels of S100-B protein in children with febrile convulsions [118]. Griffin et al. reported high levels of S100B proteins in patients with epilepsy and S100B protein could be a significant factor in the epilepsy pathophysiology [119].

CONCLUSION AND FUTURE PERSPECTIVES

The S100B is a RAGE and TLR-4 receptor-binding protein that initiates multiple intracellular signaling pathways and regulates transcription factors leading to MAPK pathway activation resulting in cell survival, proliferation, and gene up-regulation. 

The Zn2+ and Ca2+binding S100B protein producing NO in response to iNOS can lead to excitotoxicity, inflammation, oxidative stress, and mitochondrial dysfunction that leads to neuronal death in PD. 

Extracellularly administered S100B has been shown to produce a beneficial effect in TBI stimulating neurogenesis, neuronal plasticity with learning and memory improvement. 

An increased serum concentration of S100B has been reported as a characteristic of neuronal damage in MS and epileptic brain. The useful biomarker S100B in the pathology of a neurological disorder can be used as a diagnostic parameter as well as a therapeutic target in neuroscience studies. S100B has shown dual actions at low and high concentrations, being neurotrophic and neurotoxic respectively. Serum S100B level is a useful marker found in the pathology of various neurological disorders. 

An elevated level of protein initiates an inflammatory cascade that worsens the disease condition. So, targeting S100B and its receptor RAGE could be beneficial for the treatment of neurological disorders (Fig. 4).

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