The immune system can be classified into two main components, namely the cellular and humoral systems. In general, the cellular immune system is composed of macrophages, neutrophils, natural killer cells, and dendritic cells [45]. On the other hand, within the CNS, the primary components of the cellular immune system consist of glia and macrophages [46]. Glia cells have been proposed to fulfill many functions inside the CNS, including serving as a cellular repair mechanism, facilitating the removal of deceased cells, and contributing to neuroinflammatory processes [47]. Microglia and astrocytes are essential components in the preservation of neuronal integrity. Microglial cells contribute to the neuroinflammatory response in the CNS by releasing chemokines and cytokines with pro-inflammatory properties, including IL-1$\beta$, IL-6, and TNF-$\alpha$. Additionally, they have a role in modulating the response of T-lymphocytes to pathogens [48, 49, 50, 51, 52]. It has been proposed that the biological function of astrocytes may have an impact on the blood-brain barrier, perhaps leading to an increase in T-cell permeability [53]. Glia cells have been observed to be prevalent in several neurological conditions, including neurodegenerative illnesses and cerebral ischemia [54]. TLRs interact as pattern recognition receptors with exogenous ligands and endogenous molecules or danger associated molecular patterns (DAMPs) that are released upon tissue injury and cellular stress [55]. In humans, the total number of TLRs is 11, and these receptors can be categorized according to their capacity to identify specific infections. For instance, it has been observed that TLR1 and TLR2 exhibit recognition capabilities for distinct lipopeptides, TLR3 demonstrates recognition of viral RNA, and TLR4 is responsible for recognizing bacterial lipopolysaccharides. It is worth noting that TLR activation can also occur through endogenous chemicals released by damaged cells [56]. Upon activation of TLRs on microglia and astrocytes, it triggers the production of pro-inflammatory mediators, which in turn promotes the synthesis of inflammatory cytokines through the activation of various signaling pathways. These pathways include NF-kB, mitogen-activated protein kinase (MAPK), p38 extracellular signal-regulated kinase (ERK), and interferon regulatory factor 3 (IRF3) [57]. The stimulation of brain inflammatory markers is ultimately achieved through the involvement of many signaling pathways [58]. The activation of TLRs has been proposed to trigger a specific signaling pathway that is contingent upon the cell type, the unique environment, or the cellular adaptors involved. Hence, it has been proposed that the activation of TLRs could exhibit either neuroprotective or pathogenic effects, contingent upon the specific circumstance being considered. In the context of ischemia illnesses affecting the CNS, such as acute ischemic stroke [59], intracerebral hemorrhage [60], cerebral palsy [61], and epilepsy [61], the activation of TLRs has been observed to initiate an inflammatory cascade that may exacerbate the ischemic injury [60, 61]. However, it has been emphasized that the TLR plays a significant role in the regulation of glial cells phagocytic function. Studies have shown that TLRs work as receptors that facilitate communication with endogenous dying neuronal ligands, hence priming glial cells for their role in neuronal death [60]. It has been proposed that dysfunctions in the functional TLR signaling pathway may contribute to the development of neurodegeneration, as evidenced by the presence of brain lesions [61].

MYD88 refers to Myeloid Differentiation Primary Response 88, commonly known as MyD. This protein is associated with myeloid differentiation. Simultaneously, the numerical value “88” denotes the position of the activated gene within a list of five adaptors that interact with downstream signaling proteins associated with IL-1 and TLRs [62, 63]. Type I transmembrane receptors known as TLRs possess external leucine-rich repeats, a transmembrane helix, and an internal Toll/IL-1 receptor domain (TIR) [63]. TLRs are a subset of pattern recognition receptors (PRRs) that are typically triggered by pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular pattern molecules (DAMPs). Each TLR can identify certain components of pathogens. For instance, TLR4 can recognize the LPS found in the outer membrane of bacteria, whereas TLR5 can identify flagellin, a protein present in bacterial flagella [64, 65]. Hence, TLRs play a crucial role in the activation of innate immunity, leading to the initiation of inflammatory reactions and the development of antigen-specific adaptive immunity [66]. In general, TLR signaling pathways can be categorized into two main groups: MyD88-dependent pathways and MyD88-independent pathways, which are distinguished by the recruitment of certain adaptors. In relation to the MyD88-dependent pathway, it is noteworthy that all Toll-like receptors (except for TLR3) rely on MYD88 for the activation of downstream signaling. This process, known as “Myddosome”, is responsible for activating NF-$\kappa$B and AP-1 [67]. MyD88 consists of three primary domains: a death domain (DD), an intermediary domain (INT), and a Toll/interleukin-1 receptor (TIR) domain. The N-terminal DD is responsible for binding to IRAK4 (IL-1R-associated kinase), while the C-terminal TIR domain binds to the receptor’s TIR domain. It has been observed that the absence of the INT domain is correlated with the inability of MyD88 to facilitate signaling [68, 69]. In addition, TIRAP (Toll/IL-1 receptor domain-containing adapter protein), alternatively referred to as Mal (MyD88 adapter-like), serves as an intermediary for certain Toll-like receptors (TLRs) in the recruitment of MyD88 [70, 71]. The contact between a ligand and its corresponding receptor leads to the formation of receptor dimers. These dimers then bind MYD88, resulting in the activation of IRAK1 or IRAK2 through the kinase IRAK4, which has a death domain [72]. After undergoing auto-phosphorylation, IRAK1/IRAK2 dissociates from the receptor complex and interacts with E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6), leading to the process of ubiquitination and subsequent activation of TAK1 (transforming growth factor-$\beta$-activated kinase 1) [73]. The activation of TAK1 leads to its binding with the IKK complex, resulting in the activation of the complex through ubiquitination via phosphorylation of the IKK$\beta$subunit [74]. The IKK complex, which consists of two catalytic subunits, namely IKK$\alpha$(IKK1) and IKK$\beta$(IKK2), together with a regulatory subunit known as IKK$\gamma$ or NEMO (NF-$\kappa$B essential modulator), is involved in various cellular processes. The activation of IKK leads to the phosphorylation of I$\kappa$B$\alpha$, which serves as an inhibitor of nuclear factor-kappa B$\alpha$. This phosphorylation event occurs when NF-$\kappa$B is in an inactive state and confined inside the cytoplasm [75]. The process of phosphorylation of I$\kappa$B$\alpha$ leads to its destruction by the proteasome, resulting in the subsequent translocation of NF-$\kappa$B into the nucleus [76]. The NF-$\kappa$B protein then interacts with DNA, leading to the activation of specific genes and, as a result, initiating the process of transcription [76]. Intracellular TLRs, namely TLR7, facilitate the activation of Interferon regulatory factor 7 (IRF7) through the recruitment of TRAF3 and IKK$\alpha$, in addition to NF-$\kappa$B activation, by the protein MyD88. The transcription factor known as IRF7 is responsible for the production of type-1 Interferon [77]. Simultaneously, TAK1 initiates the activation of members belonging to the MAP3K family, namely p38, ERK, and JNK, which in turn activate AP-1 [78]. Therefore, it can be inferred that TAK1 is responsible for the activation of both the NF-$\kappa$B and MAP3K signaling pathways [79]. The MyD88-dependent pathway is responsible for the initiation of pro-inflammatory cytokine production, highlighting the crucial role of MyD88 in immune signaling. Previous pre-clinical investigations have documented that MyD88-knock out mice exhibit resistance to fatal septic shock caused by LPS. Furthermore, MyD88-deficient macrophages were seen to lack the ability to generate pro-inflammatory cytokines upon LPS stimulation, despite the activation of MAPK and NF-$\kappa$B signaling pathways [80]. Additionally, comparable outcomes were observed in mice that lacked TIRAP and IRAK4, as reported in previous studies [81, 82]. These results were repeated with anti-inflammatory medications that target the MyD88-dependent pathway. Hence, MyD88 has been identified as a promising therapeutic target due to its ability to mitigate inflammatory reactions mediated by MyD88. Recent studies have demonstrated that MyD88 exhibits beneficial effects in various pathological conditions, such as cancers, Ischemia-Reperfusion Injury, inflammatory diseases, blood-brain barrier dysfunction, and inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD). Additionally, it has been identified as a potential antiviral therapy by activating IRF3/IRF7 and facilitating the type-I-IFN response [83, 84, 85, 86, 87, 88, 89, 90].

The TIR-domain-containing adapter-inducing interferon-$\beta$ (TRIF), also known as TICAM1, is an additional adaptor protein associated with TLRs that facilitates the MyD88-independent signaling pathway [91]. The synthesis of interferon-related genes is mediated by TRIF-dependent signaling. The TRIF-related adaptor molecule (TRAM), also known as TICAM2, functions as an intermediary adapter to facilitate the recruitment of TIRF to TLR4. In contrast, TIRF is attracted to TLR3 in a direct manner, without the use of an adaptor protein [92]. Following the binding of a ligand, the ubiquitin ligase TRAF3 is recruited. Consequently, the activation of TBK1 and IKKi kinases is triggered, resulting in the phosphorylation of IRF3. This event facilitates the translocation of IRF3 to the nucleus, ultimately leading to the expression of type-I-IFN genes. In addition, it should be noted that TRIF plays a crucial role in the recruitment of TRAF6, hence triggering a subsequent activation of NF-$\kappa$B and MAPK signaling pathways during the late phase. This activation is facilitated by the kinase protein RIP1, also known as receptor-interacting protein [93]. The sterile $\alpha$ and armadillo-motif-containing protein (SARM) has been recognized as an additional adaptor protein involved in the signaling of TLRs. SARM functions as an inhibitor of TRIF-mediated signaling specifically for TLR3 and TLR4 [94].

Interleukin-6 (IL-6) is a cytokine that has pleiotropic effects and has gained significant recognition for its pivotal involvement in maintaining the pathophysiological equilibrium of the central nervous system and regulating glial function [95]. In the brain, under typical physiological circumstances, there exists a diminished concentration of IL-6 [95]. Nevertheless, the protein expression and release of this particular entity exhibited a favorable correlation with several neurological illnesses, including brain cancer, AD, PD, MS, and brain ischemia [96]. The pleiotropic biological effects of IL-6 on target cells are facilitated by its contact with the non-signaling membrane-bound receptor, IL6R [97]. In comparison to the receptor for Lipocalin-2 (LCN2), the expression of the receptor specific to IL6R was observed to be relatively restricted inside nervous tissue. Specifically, IL6R was mostly detected in microglia, while its presence was not observed in oligodendrocytes or astrocytes [98]. The IL6R is also present in a soluble form, which is produced through either alternate splicing of its mRNA or proteolytic cleavage from the cell membrane [99]. At the molecular level, it can be observed that IL6R does not possess the inherent ability to transmit signals downstream. Therefore, it elicits its chemical cascades via two distinct signaling channels, namely the canonical signaling pathway and the trans-signaling pathway. In the conventional signaling pathway, the cytokine IL6 engages in interaction with a particular glycoprotein receptor called IL-6 receptor-$\alpha$ (IL-6R, CD126), resulting in the formation of a high-affinity complex between IL-6 and IL-6R [98]. The complex then interacts with a transmembrane signal-transducing glycoprotein known as gp130, facilitating its dimerization and subsequent activation of intracellular signaling pathways. These pathways include JAK/STAT, ERK, and PI3K, which ultimately result in the expression of genes dependent on IL-6 and various cellular responses such as proliferation, migration, and metabolic alterations [99]. The trans-signaling route involves the interaction between the soluble IL6 receptor (sIL6-R) and IL-6, leading to the activation of distant cells expressing gb130. These cells are commonly found in neuronal cells, endothelial cells, and oligodendrocytes [100].

Chemokines are a group of extracellular pro-inflammatory proteins that function as chemotactic agents, stimulating cellular communication within the immune response. Additionally, they have a role in the establishment of neuronal networks, synapse development, and the regulation of cognitive function [101]. The classification of chemokine subfamilies can be determined by analyzing the structural motifs of the N-terminal cysteine residues. These subfamilies are categorized as CC-, CXC-, XC-, and CX3C [102]. Multiple chemokines can bind to either one receptor or multiple receptors. These receptors can be categorized based on their ligands into chemokine receptors CCR (1-10), CXCR (1-7), XCR1, and CX3CR1 [103]. Therefore, chemokines have the potential to serve as chemotactic mediators in various biological processes [104]. The CNS possesses a distinct anatomical arrangement, which is delineated from other bodily organs by the presence of colony- stimulating factor (CSF). The CNS has cellular compartments, including T cells, which exhibit a deficiency in humoral immunity to uphold an immunosuppressive milieu. During instances of neuronal damage, glial cells become activated and initiate inflammation in the CNS by releasing chemokines. These chemokines serve to attract T-lymphocytes, which infiltrate the affected area. Additionally, glial cells facilitate communication between neurons to maintain proper brain function. However, it is worth noting that the levels of these chemokines have been found to be linked to the development of many CNS diseases [105]. The activation mechanism of glia cells involves the activation of various signaling pathways through trans-membrane G protein-coupled receptors. These pathways include the activation of mitogen-activated protein kinases (MAPKs) and phospholipase C, which leads to the release of intracellular Ca ions. This release of Ca ions plays a role in modulating gene regulation, among other pathways [106, 107, 108]. Chemokines are observed within the CNS in the form of pro-inflammatory cells, serving a protective function against neuronal injury. Nevertheless, it has been documented that chemokines also contribute to the development of many neurological illnesses [109]. CX3CL1, a chemokine of considerable interest in scientific research, has a distinctive characteristic by selectively binding to a singular receptor, CX3CR1. The central CNS concentrations of this chemokine are subject to conflicting interpretations and opinions among the academic community. The CX3CL1-CX3CR1 signaling pathway has the potential to stimulate microglia, leading to the release of inflammatory substances and exacerbating the pathological condition in various neurological illnesses, including mesial temporal lobe epilepsy (MTLE), AD, PD, and amyotrophic lateral sclerosis (ALS). During the occurrence of MTLE, which is distinguished by an intense inflammatory reaction, the activation of microglia was found to be linked to the recurrent initiation of seizures, heightened neurogenesis, and synaptic remodeling [110, 111]. Elevated concentrations of CX3CL1 were observed in both blood and CSF of individuals diagnosed with mesial temporal lobe epilepsy (MTLE). Experimental studies have indicated that the absence of the CX3CR1 receptor leads to a decline in microglial activation and a decrease in the quantity of degenerated neurons [111]. The CX3CL1-CX3CR1 signalling route has been implicated in the pathogenesis of neurodegenerative illnesses. It has been observed that dysfunction of this signalling system tends to augment the activation of microglia. The chemokine signalling system has been proposed to undergo modifications in AD, resulting in an elevated population of activated microglia and the subsequent production of inflammatory markers, including IL6. Thus, it was discovered that modifying the signalling route will lead to an increasing amount of amyloid-$\beta$, which creates neurotoxicity that impacts cognitive dysfunction that is known as AD [112, 113]. In contrast, a number of studies have examined the CX3CL1-CX3CR1 signaling pathway in the context of cerebral ischemia. These studies have indicated that elevated levels of CX3CL1 have the potential to inhibit the activation of microglia cells. Consequently, this inhibition may result in neuroprotective effects by reducing the expression of inflammatory markers, including IB-1 and TNF-$\alpha$ [114, 115, 116]. In addition, the disruption of the signaling pathway through the deletion of CX3CR1 resulted in an elevated production of IL-1$\beta$ and exacerbated cerebral ischemia. The CX3CL1-CX3CR1 signaling pathway exhibits a dualistic nature, capable of exerting either neurotoxic or neuroprotective effects. The influence of pathological conditions inside the CNS on CX3CL1 levels and its receptor is contingent upon the specific type of illness.

Lipocalin-2 (LCN2) is classified as a low molecular weight acute phase protein that is a member of the lipocalin superfamily. This superfamily encompasses a total of 20 soluble proteins [117]. The substance referred to as neutrophil gelatinase-associated lipocalin (NGAL) or 24p3 is primarily synthesized and released by astrocytes, serving as a robust indicator of reactive astrocytes. Like other proteins implicated in inflammation, LCN2 is upregulated in reaction to diverse inflammatory and harmful stimuli, including as infection and damage [118]. Furthermore, the release of LCN2 by glial cells in response to various inflammatory stimuli enhances and controls neuroinflammation by activating the transcriptional processes of inflammatory chemokines and subsequently attracting immune cells [119]. Nevertheless, the function of LCN2 is facilitated by its interaction with hydrophobic ligands known as LCN2R, which enables the regulation of several cellular processes either by autocrine or paracrine mechanisms. The cellular processes may include cellular proliferation, differentiation, migration, and survival. Furthermore, the expression profile of LCNR2 exhibits significant upregulation in several neurological tissues, including neurons, microglia, and astrocytes. Thus, LCN2 is acknowledged to be elevated in numerous clinical disorders linked with the central nervous system, such as brain injury [52, 120, 121]. At the molecular level, it has been observed that the activation of LCN2 elicits the initiation of many inflammatory signaling pathways, the majority of which are facilitated by NF-Kb, MAPK, STATs, C/EBP, and HIF-1 [122]. Furthermore, the engagement between Lcn2 and LCN2R leads to the enhancement of the molecular signaling pathways involving JAK-STAT3 and IKK/NF-kB. This, in turn, triggers the transcriptional activities of various genes associated with the maintenance of glial cell integrity, including CXCL10, GFAP (glial fibrillary acidic protein, a constituent of the cytoskeleton), and ITGB3 (integrin beta chain beta 3).

IL-6 is a cytokine with pleiotropic effects that has gained significant recognition for its pivotal involvement in the pathophysiological regulation of the central nervous system and glial function [123]. In the brain, there exists a basal level of IL-6 under typical physiological circumstances [124]. Nevertheless, previous studies have established a favorable association between the production and release of this protein and several neurological illnesses, including brain cancer, AD, PD, MS, and brain ischemia [94]. The pleiotropic biological effects of IL-6 on target cells are facilitated by its contact with the non-signaling membrane-bound receptor, IL6R [95]. In comparison to the receptor for LCN2, the expression of the receptor specific to IL-6 (IL6R) was observed to be relatively restricted inside nervous tissue. Specifically, IL6R was predominantly detected in microglia, whereas its presence was not identified in oligodendrocytes or astrocytes [96]. The IL6R can also be detected in a soluble state, which is produced through two mechanisms: alternate splicing of its mRNA or proteolytic cleavage from the cell membrane [97]. At the molecular level, it can be observed that IL6R exhibits a deficiency in its ability to generate intrinsic downstream signals. Therefore, it initiates its molecular cascades by either the traditional or trans-signaling pathways. In the conventional signaling pathway, the cytokine IL6 engages in interaction with a particular glycoprotein receptor called IL-6 receptor-$\alpha$ (IL-6R, CD126), resulting in the formation of a high-affinity complex between IL-6 and IL-6R [98]. The complex interacts with a transmembrane signal-transducing glycoprotein known as gp130, which facilitates its dimerization and subsequently activates intracellular signaling pathways, including JAK/STAT, ERK, and PI3K. This activation leads to the expression of genes dependent on IL-6 and various cellular responses such as proliferation, migration, and metabolic changes [99]. In the trans-signaling pathway, the soluble IL6 receptor (sIL6-R), which is not bound to the cell surface, can form a complex with IL-6 and stimulate distant cells expressing gb130. These cells are often found in neuronal cells, endothelial cells, and oligodendrocytes [100].

Dementia is the term used to describe the decline in cognitive functioning that impairs an individual’s ability to carry out typical daily activities [125]. Neurological illnesses such as brain vascular diseases, brain damage, and dementia with Lewy’s bodies have been identified as contributing factors to its development [126]. Around 60% to 70% of dementia instances were detected in patients diagnosed with AD [125]. AD is a neurodegenerative disorder characterized by progressive cognitive decline and is recognized as the primary contributor to memory impairment [125]. In certain instances, the use of AD medication has been associated with the development of psychological problems, including schizophrenia. The etiology of AD remains elusive; nevertheless, a prominent clinical characteristic is the development of senile plaques inside the cerebral tissue [126]. The aforementioned plagues played a role in the initiation of neuroinflammation within the brain tissue [126]. The presence of neuroinflammation in AD was initially observed during the early 20th century through postmortem brain examinations conducted by Alois Alzheimer, a neuropathologist from Germany. Subsequently, there has been a comprehensive investigation into the neuroinflammation process in patients and models of AD [127]. This section aims to elucidate the involvement of inflammatory mediators in the interaction between neurons and glial cells in AD. In the context of axonal sprouting, synaptogenesis, and nervous tissue regeneration, it is crucial to acknowledge the significant role played by chemokines, which are inflammatory mediators produced by supporting cells and glial cells within the nervous system [128]. During instances of brain tissue injury, the pro-inflammatory neurotoxic cytokines, namely TNF-$\alpha$, initiate a response in astrocytes and microglial cells subsequent to the neural cells being harmed by nitric oxide free radicals [129, 130]. From a physiological standpoint, it has been seen that microglial cells and other cells within neural tissue have the ability to secrete chemokines. These chemokines are tiny proteins that possess chemoattractant properties and bind to heparin. This information has been documented in a study [131, 132, 133]. The chemokines in question exhibit the ability to bind to their respective receptors, thereby promoting cellular migration towards the site of inflammation through interactions with cell membrane proteins, namely integrin and laminin, via their extracellular matrix ligands [133, 134]. Under typical circumstances, microglial cells and astrocytes possess the ability to eliminate the pathogenic stimuli and facilitate tissue regeneration. Nevertheless, it has been observed that the cytokines released by glial cells in AD are unable to eliminate the harmful A$\beta$ amyloid plaques [135, 136, 137]. The procedure, which did not achieve its intended outcome, elicits a response from microglial cells and astrocytes, resulting in an increased release of cytokines. This, in turn, leads to damage in brain tissue, subsequently subjecting the brain tissue to repeated episodes of inflammation. Furthermore, microglial cells play a crucial role in the maintenance of the neural network and synapse function through the release of brain-derived neurotrophic factor (BDNF) [138, 139]. Therefore, it is proposed that the malfunction of microglial cells is responsible for axonal degradation and the inability of axonal regeneration in AD [140, 141, 142]. Microglial cells directly affect the brain tissue in AD, whilst astrocytes effect the blood-brain barrier (BBB). Astrocytes, which constitute the predominant neuronal population in the brain, play a crucial role in regulating the permeability of the BBB [143, 144, 145]. During instances of brain damage, astrocytes exhibit an augmented permeability of the BBB, facilitating the entry of pro-inflammatory mediators that launch the inflammatory process. Nevertheless, in the case of AD, the BBB permeability becomes excessively heightened because of recurrent cycles of inflammation inside the brain tissue [146, 147, 148, 149, 150]. As a result, neurotoxins can infiltrate the brain tissue, leading to additional harm to the tissue [151]. It is worth noting that there was a correlation observed between astrogliosis and cognitive impairment [152]. Non-steroidal anti-inflammatory medications (NSAIDs) have been widely employed in AD research as therapeutic interventions due to the prevalent involvement of neuroinflammation as a pathogenic mechanism in both AD patients and models. Regrettably, although demonstrating favorable outcomes in pre-clinical investigations, nonsteroidal anti-inflammatory drugs (NSAIDs) did not yield substantial protective effects in clinical trials [153]. Currently, individuals diagnosed with AD are prescribed medication that targets symptoms associated with the disease, such as anti-epileptic and antidepressant drugs, based on the specific issues experienced by the patient.

ASD is distinguished by enduring impairments in both verbal and nonverbal communication, as well as repeated behavioral patterns, hobbies, or activities [154, 155]. According to recent research, the prevalence of ASD is approximately 1 in 100 children, with a significantly higher occurrence in boys compared to females, with a ratio of 4–5 to 1 [156]. The etiology of ASD is multifaceted and may involve a combination of genetic and environmental influences [157]. Several environmental factors related to ASD have been found, including the presence of an inflammatory reaction [158]. The interaction between the CNS and the immune system, encompassing both innate and adaptive immunity, occurs continuously throughout an individual’s lifespan and developmental stages. This dynamic relationship is commonly referred to as neuroimmunity [159]. The influence of the maternal immune system on fetal brain development is believed to have a significant impact on the occurrence of ASD [160]. There are other variables that contribute to the dysregulation of maternal immunity, including viral and bacterial infections [161]. The correlation between prenatal ASD and maternal infection is contingent upon the specific pathogen involved as well as the timing of the infection. Research has indicated a correlation between the occurrence of bacterial infection during the second trimester of pregnancy and the development of ASD. Conversely, viral infection has been found to relate to the first trimester of pregnancy in relation to ASD [162]. It is noteworthy that the virus does not manifest in the fetal brain, indicating that the materials associated with the maternal immune response hold greater significance compared to the infection itself. One piece of evidence that supports the link between maternal immune response and fetal ASD is the detection of cytokines in the blood of the fetus. The transmission of cytokines from the mother to the fetus can occur via the placental barrier, or alternatively, fetal cytokines may be generated because of maternal cytokine activity [163]. The impact of cytokines on prenatal brain development is shown regardless of whether they originate from the maternal or fetal source [164]. An excessive production of pro-inflammatory cytokines, including tumour necrosis factor-$\alpha$ (TNF-$\alpha$), interleukin-6 (IL-6), and IL-17, was observed in children diagnosed with ASD as compared to a control group of individuals of the same age [165]. In addition, the Childhood Autism Rating Scale (CARS) was employed to discern the varying degrees of ASD severity by measuring plasma cytokine levels. Elevated levels of IL-12p40 were shown to be correlated with a less severe manifestation of ASD, whereas increased levels of TNF-$\alpha$were observed in cases of moderate severity [166]. A prior investigation conducted on deceased individuals’ brains revealed elevated levels of IL-6 in brain samples obtained from patients diagnosed with ASD [167]. The cytokine mentioned in reference [168] exerts an influence on synapse development, impulse transmission, and the morphology of dendritic spines. Prior research has indicated that a specific immune cell known as CNS microglia, which originates from the monocyte/macrophage lineage, not only participates in inflammatory responses but also contributes to neurological development. This immune cell has been implicated in the development of ASD [169]. It is worth noting that activated microglial cells were observed in the dorsolateral prefrontal cortex and other brain regions of individuals diagnosed with ASD [170]. Additionally, a study conducted postmortem revealed a notable augmentation in both the quantity and functionality of microglial cells within the cerebellum and midfrontal regions of individuals diagnosedss with ASD [171]. Within the cerebral cortex, microglial cells that have been stimulated create nitric oxide (NO), resulting in a reduction and deactivation of natural killer (NK) cells [172]. A prior investigation demonstrated a decrease in NK cell activity among individuals diagnosed with ASD [173]. In the context of autoimmune illnesses, it has been observed that maternal IgG can traverse the placenta, engage with fetal brain proteins, and thus heighten the likelihood of ASD in the developing fetus [174]. The microbiota presents in the gut, also known as normal flora, can activate the immune system in the initial year of an individual’s existence, as well as influence the activity of microglial cells [175]. The prevalence of dysbiosis, characterized by an imbalance in the composition of microbiota, was found to be elevated in individuals diagnosed with ASD [176]. Bacteroides and Clostridia are widely recognized as the predominant gut microbiota. The administration of these species as a probiotic to individuals with ASD has been found to promote communication and mitigate repetitive behaviors in this population [177]. To be more precise, the activation of the maternal immune system by antigens has been found to result in fetal brain malformation, which has been associated with the development of ASD.

Seizures refer to the occurrence of abnormal neuronal excitation or inhibition inside the brain, resulting in the development of abnormal hypertonic or hypotonic states [178]. The exact cause of seizures remains uncertain; however, several risk factors have been identified as contributors to aberrant brain activity, including but not limited to high-grade fever, head trauma, and metabolic illnesses [179]. Epilepsy is characterized by the occurrence of recurrent unstimulated seizures [180]. There exist various clinical manifestations of this condition, each exhibiting distinct levels of severity and prognosis. Examples include absence epilepsy, generalized tonic-clonic epilepsy, and benign newborn convulsions. The etiology of epilepsy often involves brain tissue injury, with neuroinflammation being a commonly reported pathogenic mechanism in this disorder. The signs of inflammation, brain tissue damage and enhanced glial cell activities have been identified in several brain locations in epilepsy [181]. Previous research has documented a notable increase in microglial activity, with the presence of cytokines being identified in brain tissue as soon as 4 hours after the occurrence of status epilepticus [182]. Elevated levels of inflammatory mediators, such as IL-1$\beta$, IL-6, and TNF-$\alpha$, were observed in the cerebrospinal fluid of patients experiencing febrile seizures [183]. The presence of increased levels of IL-1$\beta$, IL-6, and TNF-$\alpha$ in the hippocampal areas of the brain has been observed in studies conducted on seizures [184, 185, 186]. The histological examination of deceased individuals experiencing seizures revealed a notable augmentation in the microglial response, together with their corresponding antigens, in the CA3 region (3-fold increase) and CA1 region (11-fold increase) of the hippocampus, as compared to the control group [177]. The observations provide empirical evidence that lends support to the hypothesis positing that the permeability of the BBB is enhanced because of inflammatory mechanisms occurring within the brain during epileptic convulsions. The regulation of the blood-brain barrier is primarily governed by astrocytes. Research has demonstrated that the activity of astrocytes and the production of nitric oxide can be enhanced by IL-1$\beta$. Additionally, it has been observed that prostaglandin disrupts the structure of the blood-brain barrier and leads to an increase in its permeability [176]. As a result, leukocytes can penetrate the hippocampus of the brain and initiate an inflammatory response. The activation of microglia cells is a consequence of neuroinflammation [184]. The aforementioned cells are responsible for regulating neurological activity, with the relationship between neurons and glial cells mostly governed by fractalkine signaling pathways [178]. Prior research has documented dysregulation in synaptic, neurogenesis, and behavioral functions in animals with a deficit in fractalkine [179, 181]. The development of synaptic plasticity is facilitated by the production of BDNF by microglia. This process leads to the induction of LTP and the subsequent generation of learning behaviors [187]. Both activated microglia and astrocytes are known to secrete cytokines, including as IL-1$\beta$, TNF-$\alpha$, and IL-6 [188]. The presence of IL-1$\beta$ has been found to play a role in the induction of hyper-excitability in individuals with temporal lobe epilepsy. This effect is achieved by the reduction of the inhibitory neurotransmitter, GABA (gamma-aminobutyric acid), inside the brain tissue of affected individuals [182, 183]. Furthermore, there is evidence suggesting a connection between it and deficiencies in long-term potentiation, as seizures caused by interleukin have been found to affect the expression of post-synaptic N-methyl-D-aspartate (NMDA) receptors [183, 184]. Moreover, it should be noted that tumor necrosis factor-alpha (TNF-$\alpha$) is also secreted by glial cells in the context of ongoing inflammation. From a physiological standpoint, it has been seen that TNF-$\alpha$ has a role in promoting the release of glutamate by microglial cells and also leads to an increase in the expression of AMPA receptors. Conversely, TNF-$\alpha$has been found to induce the internalization of GABA receptors. As a result, the presence of TNF-$\alpha$ leads to an augmentation of brain excitatory transmission and a reduction in neural inhibition [185, 186, 189, 190]. Hence, the presence of excessively increased levels of TNF-$\alpha$ plays a role in the induction of synaptic over-excitability in the context of seizures. Epilepsy has been found to be associated not only with inflammation of brain tissue, but also with the presence of systemic inflammatory illnesses, which can also trigger the onset of epilepsy. The prevalence of epilepsy in individuals diagnosed with systemic lupus erythematosus (SLE) was found to be nearly three times higher when compared to the control group, as reported in a study [188]. SLE is known to induce brain vasculitis, leading to structural disruption to the BBB and subsequent infiltration of inflammatory mediators into the brain tissue [191]. The prevalence of epilepsy was found to be elevated in several systemic inflammatory disorders, such as rheumatoid arthritis (with a 1.27-fold increase) [192] and type I diabetes mellitus (with a 2.2-fold increase) [193]. The co-occurrence of neuroinflammation and systemic inflammation disorders has been found to be linked to the development of epilepsy.

MS is a complex neurodegenerative and inflammatory disorder that is characterized by recurrent inflammatory episodes leading to demyelination and damage to axons [194]. MS is characterized by three distinct patterns, namely relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). RRMS is distinguished by the occurrence of recurring episodes that are followed by periods of remission. These remission periods have the potential to develop into SPMS. On the other hand, it is plausible that it could manifest as PPMS. The manifestation of MS symptoms is contingent upon the location of demyelination and might manifest as cognitive, motor, or sensory dysfunction [195, 196, 197, 198, 199]. The CNS lesions manifest as demyelination plaques located in both the white and grey matter [200]. Historically, MS has been widely acknowledged as a T-cell-mediated immunological disorder [201]. The involvement of B-cells and innate immunity in the pathophysiology of MS has been widely recognized [202]. The detection of B-cells and macrophages in MS lesions has been substantiated [202]. The process of pathogenesis begins with the invasion of CD4+ cells in the white matter, facilitated by the compromised integrity of the BBB. The expansion of CD4+ cells is facilitated by the presence of IL-1, IL-6, IL-12, and IL-23, which are produced by dendritic cells, microglia, and macrophages derived from monocytes. These cytokines facilitate the recruitment of extra macrophages produced from monocytes into the CNS, resulting in the rupture of the BBB [203]. The enlarged T-cells can be categorized into two distinct kinds, namely T helper 1 (Th1) and T helper 17 (Th17) cells. The cells are responsible for the secretion of IL-17 and IL-12, which in turn contribute to the amplification of the Th17 cell through a feedback mechanism. Furthermore, Th1 and Th17 produce granulocyte-macrophage colony-stimulating factor (GM-CSF), INF-$\gamma$, and TNF-$\alpha$, which stimulate microglial cells to create IL-8. This cytokine serves the purpose of attracting neutrophils to the specific location of inflammation, while also stimulating their synthesis of metalloproteinases and chemokines. The process of demyelination and axonal injury is initiated by the combined action of INF-$\gamma$, IL-17, chemokines, and metalloproteinases [200]. A previous study has demonstrated that the inhibition or neutralization of IL-17 and INF-$\gamma$ leads to a reduction in the production of lesions in the CNS of patients with MS [204]. The CD8+ cell plays a prominent role in the pathogenesis of MS lesion formation. In the observed lesions, astrocytes, neurons, and axons exhibited a significant upregulation of MHC class I expression, rendering them susceptible to the lethal impact of CD8+ cells [205]. The CD8+ cell is responsible for the induction of multiple sclerosis MS lesions by the augmentation of granzyme secretion, as well as the synthesis of INF-$\gamma$ and IL-17 [206, 207]. On the contrary, the alternative subset of T-cells known as T regulatory (Treg) cells played a role in inhibiting the establishment of MS lesions. The suppressive effects of Treg cells on autoimmune and their role in tissue regeneration have been demonstrated [208]. The frequency and activity of these cells were found to be inadequate in patients with multiple sclerosis [209]. In addition, the presence of B-cells was seen in the CSF and brain of individuals diagnosed with MS [210]. During the initial phase of the disease, the presence of the lesion was detected, however in the later stages, there was a prevalence of plasma cells [211]. B-cells have a role in the pathogenesis of MS through various mechanisms. These processes include the formation of ectopic lymphoid follicles inside the CNS, antigen presentation to CD4+ and CD8+ cells, secretion of cytokines, and generation of antibodies [202]. A study conducted in vitro demonstrated that the B-cells of individuals with MS are responsible for causing CNS demyelination and neurodegeneration [212]. The utilization of oligoclonal bands of IgG as biomarkers for MS has been previously documented, but the identification of IgM oligoclonal bands has been associated with the presence of aggressive MS [213, 214]. Meningeal and grey matter inflammation are widely recognized as the primary causative mechanisms that give rise to MS lesions, hence contributing to the development of all three clinical manifestations of the disease.

Research show that amyloid-beta (A$\beta$) and its associated proteins have a substantial impact on the disruption of the balance between E/I neuronal activity in the initial phases of AD [214]. Alterations in excitatory synaptic transmission are crucial in the manifestation of hyperactivity and hypersynchrony, hence leading to the onset and spread of epileptic seizures. The administration of soluble A$\beta$, both in vivo and in vitro, lead to hyperactivation of neurons in the hippocampus [215, 216]. The hyperactivation is facilitated by various mechanisms associated with the transmission of glutamate at synaptic sites. Soluble A$\beta$ enhances N-Methyl-D-Aspartate receptor (NMDAR) currents in the hippocampus, directly influencing neuronal firing [217, 218]. Furthermore, A$\beta$ has been found to interfere with the process of glutamate absorption by directly modifying the functioning or expression of glutamate transporters, hence leading to an elevation in the extracellular concentration of glutamate. This phenomenon results in the occurrence of sudden stimulation of post-synaptic neurons and hindered long-term potentiation [218]. Nevertheless, a decrease in the expression of the glutamate transporter has been shown to hinder the beginning and spread of seizures in epilepsy [219, 220]. The increase in APP elevation has been found to enhance the mRNA expression of NMDAR that contains GluN2B in the hippocampus [221, 222]. The activation of the GluN2B NMDA receptor has been found to be correlated with the perturbation of calcium homeostasis. Apoptosis may occur because of the unregulated elevation of intracellular Na${}^{+}$ and Ca${}^{2+}$ levels, which is triggered by the release of the NMDAR Mg${}^{2+}$ blocker due to sustained depolarization of the neuron [223]. Conversely, it has been observed that inhibitory circuits are similarly impaired in AD [127, 224]. Animal models of AD have demonstrated an imbalance between E/I neural activity following the injection of a GABAA antagonist (picrotoxin), resulting in the occurrence of seizures [128, 129]. Tg2576 rat model, when administered with an alternative GABAA antagonist known as pentylenetetrazol, exhibited the manifestation of seizures [130, 131]. These effects have the potential to lead to a decrease in the functionality of the inhibitory circuit. [132, 133]. Downregulation of certain subunits within the receptor in distinct brain areas suggests that there is a remodeling of the GABAergic receptor [134, 135]. In addition to the impact on the GABA receptor, it has been observed that the release of GABA is diminished in AD due to the presence of A$\beta$ [136].

Neurons exhibit excitability and inhibition during neurodevelopment in the forebrain are produced in distinct regions and undergo migration to atypical locations which leads to the formation of heterotopias [137]. Heterotopias, disorganized cortical patches and focal cortical dysplasia, are abnormalities seen in ASD. However, E/I neocortical imbalance may be connected to pyramidal glutamatergic neurons and the inhibitory GABAergic parvalbumin-positive interneurons [138, 139]. ASD show modifications in gene transcription, translation, and the degeneration of synaptic proteins known as neuroligins. This modification has an effect on ion channels, receptors, cell adhesion, and synaptic scaffolding proteins. Neuroligin is a cell adhesion molecule which is specifically localized to excitatory synapses through the action of neuroligin one, or to inhibitory synapses through the action of neuroligin 2 [140]. Neuroligin 3 is present in both excitatory and inhibitory synapses, whereas neuroligin 4 has been observed to be specifically localized in glycinergic synapses [141]. During in vivo study, mutation in the neuroligin 4 genes, which differs from that of humans [142, 143]. However, mice with a mutation in neuroligin 1–3 exhibited impaired transmission of GABAergic/glycinergic signals in the brainstem, both in response to external stimuli and spontaneously [144, 145]. The regulation of synaptic function is influenced by neurexin, which acts as a binding partner for neuroligin, and regulation is dependent on the specific neurotransmitter involved [225]. The trans-synaptic adhesions formed by neuroligin and its binding proteins, neurexins (Nrxns), have been implicated in ASD by facilitating the recruitment of NMDARs and AMPARs to the synapse surface [226]. A mutation in contactin-associated protein-like 2 (CNTNAP2), a protein belonging to the neurexin superfamily, is identified as a cause of childhood epilepsy, hyperactivity, and Autism. The absence of CNTNAP2 results in impairments in the process of neuronal migration and the degradation of GABAergic cells [227]. Tuberous sclerosis complex (TSC) plays a vital role as an inhibitory element within the mTORC1 pathway, which is responsible for cellular growth and preserving the balance of synaptic activity. The activity of the mTORC1 pathway is increased in ASD because of mutations in the TSC gene. However, the functional examination of neurons with TSC mutations has show conflicting results. The presence of a loss-of-function mutation in the TSC gene has been linked to a multisystem illness is characterized by neurological symptoms which is associated with ASD [228, 229]. Decrease in excitability of TSC2-/- stem cell-derived neurons reported an elevation in neuronal activity [230, 231, 232]. Significantly, the administration of rapamycin effectively rectified aberrant excitability by suppressing mTORC1 in instances when neuronal activity was heightened or diminished [233, 234]. The occurrence of haploinsufficiency in the ARID1B gene, serves as a sequence-specific DNA-binding subunit within the chromatin complexes of mammalian SWI/SNF or Brg1-associated factors (BAF) and it contribute to the development of ASD [235]. The occurrence of haploinsufficiency in ARID1B is considered as a causative factor with decrease of total GABAergic interneurons in the cerebral cortex, but cortical pyramidal neurons do not show major alteration which is the concept of E/I [236] The cognitive impairment observed in Arid1b-deficient mouse models resembled the behavioral pattern associated with ASD [237]. Based on recent study, ARID1B regulatES Wnt/$\beta$-catenin signaling in HEK293T cells [237, 238].

Epilepsy is distinguished by the occurrence of recurrent and unprovoked seizures [239]. Epilepsy has a global prevalence rate of 1% among the general population [238]. The equilibrium between E/I synapses is crucial for regulating synaptic activity. And Epilepsy is characterized by an imbalance in electrical activity, which arises due to a decrease in inhibitory GABA synaptic and voltage-gated conductance, as well as an increase in excitatory glutamate synaptic and voltage-gated conductance [239, 240]. Glutamatergic neuronal activity is referred to as the glutamate hypothesis. And even basic anomaly in the pathogenesis of epilepsy [240, 241]. The administration of Pilocarpine at a dosage of 40 mg/kg intraperitoneally shows persistent seizure-like behavior in mice which is through activation of the M1 receptor [242]. The resulting seizure-like behavior is primarily mediated by the activation of NMDA receptors, which subsequently leads to the development of temporal lobe epilepsy (TLE), secondarily generalized seizures, and status epilepticus [130, 131, 132, 133, 134, 135, 136, 137, 138]. The activation of receptors has a crucial role in the establishment of long-term synaptic plasticity and coordinated firing, although its significance in the preservation of epileptic convulsions is limited [139, 243]. High influx of calcium ions (Ca${}^{2+}$) into the neuron via NMDA-dependent calcium channels has been observed in cases of epilepsy [244]. This influx leads to the generation of ROS, which subsequently leads to an elevation in mitochondrial permeability transition [245, 246]. This leads to swelling of the mitochondria and the hydrolysis of ATP, which ultimately result in the demise of the affected neurons [245, 246]. The overexpression of mGluR group I/II has been observed in both epileptic individuals and animal models. The presence of these receptors has been observed in hippocampal neurons and astrocytes, and also associated with the regulation of glutamate and GABA neurotransmission as well as the interaction between astrocytes and neurons [247]. The release of Ca${}^{2+}$-dependent glutamate from astrocytes in a spontaneous manner has the potential to enhance the activity of metabotropic glutamate receptors (mGluRs) by augmenting glutamatergic neurotransmission in the terminals of presynaptic neurons [248, 249]. Multiple anticonvulsant medications effectively mitigate epileptic activity through the attenuating Ca${}^{2+}$ signaling inside astrocytes. Moreover, they exhibit antagonistic effects on NMDAR and AMPAR. Postmortem studies in patients with epilepsy have indicated substantial change in the expression and trafficking of GABAA receptors [244]. Nevertheless, epileptiform activity has been observed to induce changes in the intracellular concentration of Ca${}^{2+}$ and a role in the pathological processes associated with status epilepticus (SE) [245]. In addition, activation of calcineurin leads to GABAA receptors trafficking in neurons during epileptiform activity. The depletion of GABAergic interneurons can lead to a reduction in tonic inhibition in rat hippocampal neuronal cultures which were subjected to persistent epileptogenic stimulation [246]. In contrast, individuals with TLE have a disruption in the regulation of Cl${}^{-}$ levels and this disruption indicates show improper functioning of the Na-K-2Cl transporter (NKCC1) which is responsible for facilitating the influx of Cl- ions, K-Cl cotransporter (KCC2) and facilitating the efflux of Cl- ions [247]. The activation of flux leads to an increase in the excitability of granule cells and a decrease in the effectiveness of inhibitory synapses. In recent study the expression of NKCC1 in epileptic tissue was high, whereas the expression of KCC2 was shown to be diminished [244, 248, 249, 250]. The reduction in the effectiveness of GABA inhibitory action can be attributed to the downregulation of KCC2, which is facilitated by the activation of the TrkB receptor through BDNF [251].

Still, intense research is needed to understand the importance of glutamatergic and GABAergic systems in MS [252]. MS involves glutamate-mediated excitotoxicity, wherein neuronal death occurs due to excessive activation of glutamate receptors and subsequent increase in intraneuronal calcium levels [253, 254]. The extracellular level of glutamate is elevated due to the overproduction of glutamate by macrophages and microglial cells [255] and decrease in the breakdown of glutamate by oligodendrocytes [256]. The increase in extracellular glutamate levels initiate the glutamate signaling pathway by activating glutamate receptors present in neurons, oligodendrocytes, and astrocytes [257]. Therefore, the increase in extracellular glutamate adversely affects all of these cellular populations. Furthermore, an excessive amount of glutamate stimulates both NMDA and non-NMDA receptors, causing an aberrant buildup of intracellular calcium ions, which ultimately leads to neuronal harm [258, 259]. The utilization of magnetic resonance spectroscopy (MRS) imaging methods helps in identification of increased levels of glutamate in the active lesion located in the white matter. Conversely, individuals with MS exhibit a diminished concentration of glutamate in the grey matter when compared to individuals without the condition [260]. Based on findings, by decreasing the quantity of glutamate in the grey matter, it led to neuronal and synaptic degeneration [261, 262]. Excitotoxicity can arise not only due to an excessive concentration of glutamate, but also due to an inadequate presence of GABA to counteract excitatory effect. Even reduction in the extracellular concentration of GABA has been observed in individuals diagnosed with MS which is linked to deficits in both motor and cognitive functioning [263, 264]. The decrease in GABAergic neurotransmission is hypothesized to be facilitated by IL-1 in MS [265].