Targeting S100B Protein As A Surrogate Biomarker And Its Role in Various Neurological Disorders Part 1

Abstract: 

Neurological disorders (ND) are central nervous system (CNS) related complications originating from enhanced oxidative stress, mitochondrial failure, and overexpression of proteins like S100B. 

With the aging of the population, the health problems of the elderly are becoming more and more important. Among them, mitochondrial failure is one of the health problems that the elderly are very concerned about. Mitochondrial failure not only affects physical functions but may also hurt memory.

Mitochondria are organic matter in cells, and their function is to convert the energy in food into usable chemical energy for cell life activities. Mitochondrial failure will lead to insufficient energy and easily lead to a decline in physical functions, such as motor ability, immunity, and memory.

However, it should be noted that mitochondrial failure does not necessarily hurt memory. Only when the degree of damage to mitochondria is more serious will it affect memory? Different types of memory will be affected to varying degrees. For example, spatial memory and situational memory will be more significantly affected.

However, even in the face of the negative impact of mitochondrial failure on memory, we should not be discouraged. Because modern medical technology has developed to a certain extent, it can effectively help us deal with the problem of mitochondrial failure. For example, proper diet and exercise can alleviate the effects of mitochondrial failure; and electrical stimulation and drug therapy are also effective treatments.

Therefore, we should maintain a positive attitude, follow a healthy lifestyle, stay healthy, and effectively prevent and deal with health problems caused by mitochondrial failure, to maintain good memory and quality of life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

Click know ways to improve your memory

S100B is a helix-loop-helix protein with the calcium-binding domain associated with various neurological disorders through activation of the MAPK pathway, and increased NF-kB expression resulting in cell survival, proliferation, and gene up-regulation. 

S100B protein plays a crucial role in Alzheimer's disease, Parkinson's disease, multiple sclerosis, Schizophrenia, and epilepsy because the high expression of this protein directly targets astrocytes and promotes neuroinflammation. Under stressful conditions, S100B produces toxic effects mediated through receptors for advanced glycation end products (AGE) binding. 

S100B also mediates neuroprotection, minimizes microgliosis, and reduces the expression of tumor necrosis factor (TNF-alpha) but these are concentration-dependent mechanisms. An increased level of S100B is useful for assessing the release of inflammatory markers, nitric oxide, and excitotoxicity-dependent neuronal loss. 

The present review summarizes the role of S100B in various neurological disorders and potential therapeutic measures to reduce the prevalence of neurological disorders.

Keywords: S100B, neurological disorders, astrocytes, inflammatory cytokines, microgliosis, tumor necrosis factor.

1. INTRODUCTION

Neurodegenerative disorders are characterized by selective dysfunction and gradual loss of neuronal populations associated with pathologically altered protein that mainly deposits in the brain and spinal cord [1]. 

The deposition of extracellular and intracellular proteins fibrils, oxidative stress, and mitochondria dysfunction are the key pathological features of many different neurological disorders. 

Oxidative stress is indicated by the over-production of reactive oxygen species (ROS) that can cause mitochondrial DNA mutations, destroy the respiratory chain, alter the permeability of the membrane, and affect calcium homeostasis and mitochondrial protection systems [2]. 

During normal physiological conditions, 1–5% of O2 is transformed to ROS, thus most estimates have suggested that the majority of intracellular ROS are produced from mitochondria. 

Mitochondrial superoxide radicals are produced primarily in the electron-transport chain (ETC), namely complex I and II. Complex III is the main site of ROS production under normal metabolic conditions, and due to this, the free radical can attack directly the respiratory chain of the mitochondria [3]. When free radicals attack mitochondrial DNA, they can amplify oxidative stress by reducing the expression of critical proteins that are important for electron transport; this results in a vicious cycle of ROS and organ dysregulation that ultimately triggers apoptosis [4]. 

Furthermore, the ETC is especially prone to both NO- and ONOO-mediated damage. Oxidation and nitration of protein in the ETC result in altered function of many metabolic enzymes [5]. Chronic exposure to ROS may result in oxidative damage to mitochondrial and different cellular proteins, nucleic acids, and lipids, and acute exposure to ROS may inactivate complexes I, II, and III, leading to the shut-down of mitochondrial energy production which leads to death of neurons [6]. 

Nitric oxide (NO) is a key secondary cellular transporter that at nanomolar concentration inhibits the cytochrome oxidase (complex IV) enzyme activity, impairs mitochondrial metabolism, and contributes to free radical formation. 

NO reacts with these negatively charged anion particles to form peroxynitrite, which is a more harmful cytotoxic agent than NO and a mediator of vascular tissue damage and a cause of the death of neurons. In past decades, these free-charged particles have strongly been linked with neurological disorders like Alzheimer's disease (AD) [7]. 

Around, 90%-95% of the overall production of adenosine triphosphate (ATP) among aerobic cells needs oxygen. ATP synthesis via the respiratory chain of mitochondria is the outcome of electron transport across the ETC coupling oxidative phosphorylation melatonin, mitochondria, and cellular bioenergetics [8]. 

The produced superoxide ions are neutralized by the intra-mitochondrial redox systems that resist oxidative damage and, improve ATP production. Damaged mitochondria in aging and neurodegenerative diseases are not capable of meeting the required energy demand and ultimately cause the deaths of neuronal cells. 

The large amount of NO which is released from glial cells through the expression of iNOS after their stimulation is neurotoxic because it induces oxidative stress, excitotoxicity, and mitochondrial dysfunction [9]. 

In one of the reported studies when old rats' brain mitochondria were compared with those of young rats, significant endogenously decreased antioxidants and superoxide dismutase activity were found, due to excessive oxidative injury to proteins and lipids and lower mitochondrial complex I, IV, and V activities. 

The NO is a multi-target inhibitor of mitochondrial oxidative phosphorylation and more prominently inhibits complex I and II [10]. The S100B protein belongs to the mutagenic family with 25 members (like calmodulin/ parvalbumin/ troponin C) and was named because of its solubility in a 100% saturated solution of ammonium sulfate at neutral pH. 

The first member of this family was the unfractionated mixture of two proteins S100A1 and S100B [11-13]. Structurally, the S100B protein consists of two alpha helix-loop-helix calcium-binding proteins involved in cytoskeleton formation and cellular proliferation [14]. 

The other members of the S100B protein like S100A1, and S100A8 help to control multi-cellular functions like cell-cell communication, cell growth, and cardiac muscle contraction by calcium-induced calcium release (CICR) cascade [15]. The intracellular signaling of these proteins is initiated by extracellular stimuli via interacting with different cellular proteins known as target proteins [16]. 

Persistent receptor for advanced glycation end product (RAGE) activation by S100B at micromolar concentration produces oxygen radicals in high amounts that lead to mitochondrial dysfunction and apoptosis. Moreover, this concentration was reported for iNOS up-regulation to induce the release of NO and NO-dependent neuronal and glia death, facilitating glutamate-mediated death of neurons, upregulation of COX-II expression in microglia, increasing ROS production in neurons and arrest of the cell cycle [17]. 

In rats, iNOS is stimulated by S100B primarily in cortical astrocytes via the pathway of signal transduction involving transcription factor NF-kB activation. The activation of NF-kB was confirmed by p65 NF-kB subunit translocation, and NF-kB transcriptional activity stimulation [18]. Furthermore, oxidative stress due to ROS production induces mutations of the mitochondrial DNA, dysfunction of the respiratory system of mitochondria, membrane permeability alterations, and affects calcium balance and mitochondria defensive system. 

All mentioned alterations lead to the development of neurodegenerative diseases, such as AD, PD, and ALS [5]. Scientists have reported that the S100B protein controls the activation of Glial fibrillary acidic protein (GFAP), polymerization of tubulin, and DNA repair [19]. 

GFAP is a characteristic intermediate filament (IF) protein in astrocytes which are a type of macroglial cells in the CNS that control brain homeostasis in the healthy and diseased state. Astrocytes are supposed to be a reactive phenotype in acute CNS trauma, ischemia, and neurodegenerative disorders. These astrocytes activate cell protection which induces chemotaxis, pro-inflammatory cytokines release through NF-kβ and p38 MAPK signaling [20]. 

Brandt et al. in 2017 demonstrated that microtubule dysfunction relates to some of the degenerative events like synaptic impairment associated with loss of dendritic spines, dendritic simplification that is associated with the extent of microtubule stability and cell death that provides a useful target to prevent several degeneration processes in AD [21]. 

Microtubule-associated tau protein plays an important role in stabilizing microtubule assembly and cellular morphology. In AD, hyperphosphorylated tau proteins are aggregated into paired helical filaments and accumulated in the neurons with the formation of neurofibrillary tangles. Any imbalance in the regulation of S100B protein, kinases, and protein phosphatases is the direct cause of tau hyperphosphorylation [22]. So, the inhibitor of S100B protein or its down-regulation may be useful to prevent tauopathy in AD. 

The release of S100B protein in the body is controlled by metabolic stress like hypoxia or glucose deprivation during the developmental stage of the astrocytes. The release is stimulated in response to external stimuli like 5HT, glutamate, pro-inflammatory cytokines (IL-1 beta and TNF-alpha), β-amyloid peptides, lysophosphatidic acid, natural plant antioxidants (epicatechin and resveratrol) and by increased calcium concentration [23]. 

In PD, an increase in caspase-3 expression and activation of iNOS result in dopaminergic cell death and production of apoptotic bodies [24, 25]. Similarly, nitric oxide released by S100B causes astrocytes to undergo apoptotic cell death [26]. 

During the disease, S100B, alpha-beta, AGEs and RAGE ligands like TRR, HMGB1, S100A6, S100A8/A9, and S100A12 start to accumulate in the neuronal cell, more prevalent in the dopaminergic cell. 

S100B secretion and chronic activation of RAGE associated with neuropathological markers like microglia activation ROS, NFT formation, neurite degeneration, and neuronal apoptosis lead to cognitive impairment [27]. 

In schizophrenia, S100B after release from glial cells, NK cells, and CD8+ lymphocytes enhances the cytokines level and is a proposed marker of glial cell dysfunctioning. Furthermore, S100B also shows adipokine-like properties and may get unbalanced in schizophrenia due to disturbed insulin signaling which also releases free fatty acids from adipose tissue [28].

The expression of S100B is affected by aging. In the available literature, the researcher has found age-related changes in S100β expression in different species. 

Some authors have suggested an increase in the expression of S100β in the brain cortex and hippocampus by activating astrocytes with age [29]. The post-mortem study has shown that the number of S100B-positive cells and tissue which consist of S100B mRNA and S100B protein increased with advancing age. In the case of overexpression of S100β, the protein enhances the production of proinflammatory cytokines, which has a detrimental impact and contributes to neuron and glial cell apoptosis [30]. 

In addition, the hippocampus is particularly vulnerable to aging, which can contribute to spatial learning disorder, whereas other brain regions, like PAG, can function properly. These neurological disorders are possibly induced by Ca2+-dependent processes, which influence long-term depression (LTD) and long-term potentiation (LTP) [31]. 

In patients with AD, the presence of highly reactive astrocytes surrounding neuritic plaques has been observed in the temporal lobe. This protein also had an increased reactivity in patients with Down syndrome [32]. In the cortex and hippocampus parts of the brain, age and sex-related changes in S100β expression have been observed. 

Studies have shown that in female rats at the beginning of the rest phase of the regular process, the maximum expression of S100β was observed, while in male rats, it was observed at the beginning of the motor activity phase [33]. 

Older rats have increased protein expression compared with young rats. Moreover, significant differences in S100β have been observed within the differences in the region of the brain in rats. Some reports have found that SAMP mice have increased S100B in the hippocampus and cerebral cortex compared to control mice [34]. The conclusion of available data has explained that the expression of S100B is affected by aging. 

Apart from S100B, other calcium-binding proteins (CaBPs) members of the EF-hand family are parvalbumin, calretinin, and calbindin, whose functions in neurons are unknown. But these proteins have a great interest in neuroanatomy and neuropathology since immunocytochemistry for parvalbumin, calretinin, and calbindin has been shown to help characterize chemically and morphologically sub-populations of neurons in the nervous system [35]. 

Various reports have explained that CaBPs are involved in numerous activities, including cell signaling, calcium uptake and transportation, cell motility, and intracellular acceptance. Recent experiments have shown that intracellular CaBPs are important methods in central and peripheral nervous systems for investigating neuronal typology [36]. 

These proteins contain various EF-hand domains in which parvalbumin contains 3 domains and calretinin and calbindin both contain 6 domains with the binding of 3, 5, and 4 ions of calcium, respectively [37]. 

All three of these CaBPs have a strong calcium-binding ability, although their kinetics seem to vary, for example, slow-binding kinetics is reported in parvalbumin conditions. Various neuronal sub-populations are reported for expressing these CaBPs. 

Majorly, immunoreactive cells of these proteins are smooth non-pyramidal interneurons and take part in various multifaceted cortical circuits that may vary depending upon cortical area, species, or the layer where they are located [38]. In neocortical interneurons, the inhibitory neurotransmitter GABA is co-localized with these three CaBPs along with nitric oxide synthase and neuropeptides [39]. 

Among GABAergic interneurons, are parvalbumin expressed by hippocampal and cortex basket cells, cerebellum Purkinje cells, calbindin expressed by Purkinje cells of cerebellar, sub-population of the hippocampus [35, 40], and outward CA1 pyramidal neurons [41], also cortical populations. The calretinin was found initially in the retina, cortex interneurons [42], and also in the hippocampus along with granule cells in the cerebellar [33]. 

It was observed that neurons that are expressing specific CaBPs could be more susceptible to neurodegeneration. The effect of CaBP expression on neuronal susceptibility tends to be highly dependent on the disease or experimental disease model, where the severity of the brain injury, and also the specific calcium elevation pathway can play an important role [35, 43]. 

There are also many other factors involved in assessing the sensitivity of different neurons to degeneration, including, their circuit communication, trophic support network, relative synaptic inputs to extra-synaptic NMDA receptors, as well as their energy needs [40]. 

High expression of CaBPs is associated with high calcium influx rates and intracellular release. These same neurons could also be at the most risk of degeneration due to the demands of high energy. 

Furthermore, understanding the factors regulating CaBP expression and how neurons regulate this under pathophysiological conditions could allow for the development of neuroprotective strategies [40].

For more information:1950477648nn@gmail.com