**1. Introduction**

Neurons represent the main component of the nervous system, and they are indispensable for integration and transcription of nerve impulses [1]. The central nervous system (CNS) is made up of about 100 billion neurons and approximately 10–50 times more glial cells [1]. Unlike glial cells, which maintain the ability to undergo cell division even after adult age, neurons are no more capable of mitosis at the adult age. Nevertheless, they are supposed to live all the life of an individual [1]. Unluckily, there are some pathologic and physiologic circumstances during which we observe a premature neuronal death [2]. These include stroke, head trauma, neurodegenerative disease, psychiatric disease, multiple sclerosis, aging, etc. This premature neurological death caused by pathologic circumstances is what we call neurotoxicity. The biochemical mechanisms of neurotoxicity are not all described yet. Nevertheless, no matter the mechanism, the result will be either apoptosis, pyroptosis, or necrosis [3]. Reviewing the literature, we found several biochemical pathways described as being implicated in the process of neurotoxicity. These include excitotoxicity, oxidative stress, glial cell destruction, vascularization

interruption, and inflammation [3]. Being confronted with neurotoxicity, an idea emerged about possibly protecting neurons against insults using pharmacologic means. This was the birth of the neuroprotection concept.

The neuroprotection concept regroups all pharmacologic and/or physical resources capable of preventing or avoiding neurotoxicity by affecting one or more biochemical mechanisms of neurotoxicity [4, 5]. This definition excludes all therapeutics that lead to an improvement of the vascularization of the brain [4, 5]. The neuroprotection targets could therefore be avoidance of excitotoxicity, glial cell protection, oxidative stress reduction, and/or inhibition of inflammation. On the theoretical, logic and experimental fields, neuroprotection is evident; however, it remains a concept difficult to prove on the clinical field. Indeed, although many animal experimental researches on neuroprotection have been conclusive, this could not be confirmed in clinical trials. This could be explained by the difficulty to establish clinical criteria for the evaluation of neuroprotection in clinical researches. Despite this methodologic difficulty which tends to discredit the neuroprotection concept in clinical field, we propose to make an analysis of neuroprotection on the prism of inflammation. We will present a synoptic view of the inflammatory mechanisms implicated in neurotoxicity and bring out the possible implications in neuroprotection.

## **2. Inflammatory reaction and particularities in the central nervous system**

Inflammation is the first step in the defense mechanism of the organism by which the actions of different components of the nonspecific immunity are put together in order to fight against an exogenous or endogenous aggression [6]. By definition, inflammation is a local process which takes place in the connective tissue of the organ affected. Nevertheless, according to the amplitude and duration of the local inflammation, it can be secondarily generalized through production of a systemic response such as the synthesis of acute-phase reactants or the endocrine effect of cytokines [6, 7].

#### **2.1 Inflammation response mechanism**

The first step of an inflammation reaction is the adhesion of leukocytes on the endothelial membrane. This step takes place essentially in the postcapillary venule. Activated endothelial cells are required for this step as they need to express adhesion molecules on their surfaces. These molecules serve as receptor for their complementary adhesive molecules present on the surface membrane of circulating leukocytes. Leukocyte adhesion to the vascular endothelium occurs in two phases which implicate both adhesion molecules. The first phase is the leukocytes rolling on the vascular endothelium. It involves the E-selectin (CD62E) and the P-selectin (CD62P) expressed on the vascular endothelium transiently interacting the P-selectin glycoprotein ligand-1 (PSGL-1), E-selectin ligand-1 (ESL-1), and L-selectin (CD62L) which are ligands expressed on leukocytes' surface. The second phase is the leukocyte-endothelium firm adhesion. It is realized by the interaction between the vascular endothelium adhesion molecules named vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and leukocyte integrins known as VLA-4 and LFA-1 (**Figure 1**). The leukocyte adhesion is preceded by a certain number of steps which aid the adhesion phase. These steps are endothelial activation, induced by interleukin-1β (IL-1β) and tumor necrotic factor α (TNFα); the activated endothelium secretes some agents such as

**321**

**Figure 1.**

*Mechanism of inflammation reaction.*

*Neuroprotection: The Way of Anti-Inflammatory Agents DOI: http://dx.doi.org/10.5772/intechopen.90509*

platelet-activating factor (PAF), prostaglandin E2 (PGE2), and azote monoxide (NO) which lead to a vasodilatation with reduction of blood flow aiding leukocyte rolling. Interleukin-1β and TNFα are also responsible for the adhesion molecules expressed on the endothelial surface and the liberation of chemotactic agents.

and refers to the passage of leukocytes from blood circulation to the connective tissue where the inflammation process has begun. This leukocyte migration is done across the intercellular endothelial junctions and is affected by chemotactic peptide concentration gradient at the inflammatory focal point. At the inflammatory focal point, leukocytes become activated and start to secrete oxygen-reactive substances, pro-inflammatory cytokines, and lipid inflammatory mediators. They also excrete the contents of their granules. All these actions lead to a systemic inflammatory response by endocrine effects of pro-inflammatory cytokines and also cessation of the cause of the inflammation. However, in certain cases the amplification of the inflammation by pro-inflammatory cytokines is responsible of destruction of the tissue where it takes place [7]. The endocrine effects of pro-inflammatory cytokines are multiple; the principal effects are observed on the liver and the brain [8]. In the liver, they induce the synthesis of acute-phase proteins; on the brain, they result in

fever, asthenia, anorexia, and somnolence (**Figure 2**).

**2.2 Inflammatory cytokines**

The second step of inflammation is diapedesis; it follows the leukocyte adhesion

The term cytokine regroups the low-molecular-weight glycoproteins implicated in cellular communication. They are active in the control of proliferation, maturation, and differentiation of hematopoietic cells and also in the regulation of inflammatory and immunologic responses. They exercise their regulatory activity through an autocrine, paracrine, juxtacrine, and endocrine mechanism via the membrane receptors present on focus cells. In the field of immunology, there exist two groups of cytokines: pro-inflammatory cytokines such as interleukins 1, 6, 8, and 18 (IL-1, IL-6, IL-8, IL-18), TNFα and anti-inflammatory cytokines such as interleukins 10, 4, and 13 (IL-10, IL-4, IL-13) transforming growth factor β (TGFβ). The balance between pro-inflammatory and anti-inflammatory cytokines regulates the local intensity of an inflammatory reaction and its duration. Among pro-inflammatory cytokines, IL-1β and TNFα have the central role in the initiation and chronicity

*Neuroprotection: The Way of Anti-Inflammatory Agents DOI: http://dx.doi.org/10.5772/intechopen.90509*

*Neuroprotection - New Approaches and Prospects*

neuroprotection.

**system**

effect of cytokines [6, 7].

**2.1 Inflammation response mechanism**

means. This was the birth of the neuroprotection concept.

interruption, and inflammation [3]. Being confronted with neurotoxicity, an idea emerged about possibly protecting neurons against insults using pharmacologic

The neuroprotection concept regroups all pharmacologic and/or physical resources capable of preventing or avoiding neurotoxicity by affecting one or more biochemical mechanisms of neurotoxicity [4, 5]. This definition excludes all therapeutics that lead to an improvement of the vascularization of the brain [4, 5]. The neuroprotection targets could therefore be avoidance of excitotoxicity, glial cell protection, oxidative stress reduction, and/or inhibition of inflammation. On the theoretical, logic and experimental fields, neuroprotection is evident; however, it remains a concept difficult to prove on the clinical field. Indeed, although many animal experimental researches on neuroprotection have been conclusive, this could not be confirmed in clinical trials. This could be explained by the difficulty to establish clinical criteria for the evaluation of neuroprotection in clinical researches. Despite this methodologic difficulty which tends to discredit the neuroprotection concept in clinical field, we propose to make an analysis of neuroprotection on the prism of inflammation. We will present a synoptic view of the inflammatory mechanisms implicated in neurotoxicity and bring out the possible implications in

**2. Inflammatory reaction and particularities in the central nervous** 

Inflammation is the first step in the defense mechanism of the organism by which the actions of different components of the nonspecific immunity are put together in order to fight against an exogenous or endogenous aggression [6]. By definition, inflammation is a local process which takes place in the connective tissue of the organ affected. Nevertheless, according to the amplitude and duration of the local inflammation, it can be secondarily generalized through production of a systemic response such as the synthesis of acute-phase reactants or the endocrine

The first step of an inflammation reaction is the adhesion of leukocytes on the endothelial membrane. This step takes place essentially in the postcapillary venule. Activated endothelial cells are required for this step as they need to express adhesion molecules on their surfaces. These molecules serve as receptor for their complementary adhesive molecules present on the surface membrane of circulating leukocytes. Leukocyte adhesion to the vascular endothelium occurs in two phases which implicate both adhesion molecules. The first phase is the leukocytes rolling on the vascular endothelium. It involves the E-selectin (CD62E) and the P-selectin (CD62P) expressed on the vascular endothelium transiently interacting the P-selectin glycoprotein ligand-1 (PSGL-1), E-selectin ligand-1 (ESL-1), and L-selectin (CD62L) which are ligands expressed on leukocytes' surface. The second phase is the leukocyte-endothelium firm adhesion. It is realized by the interaction between the vascular endothelium adhesion molecules named vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and leukocyte integrins known as VLA-4 and LFA-1 (**Figure 1**). The leukocyte adhesion is preceded by a certain number of steps which aid the adhesion phase. These steps are endothelial activation, induced by interleukin-1β (IL-1β) and tumor necrotic factor α (TNFα); the activated endothelium secretes some agents such as

**320**

**Figure 1.** *Mechanism of inflammation reaction.*

platelet-activating factor (PAF), prostaglandin E2 (PGE2), and azote monoxide (NO) which lead to a vasodilatation with reduction of blood flow aiding leukocyte rolling. Interleukin-1β and TNFα are also responsible for the adhesion molecules expressed on the endothelial surface and the liberation of chemotactic agents.

The second step of inflammation is diapedesis; it follows the leukocyte adhesion and refers to the passage of leukocytes from blood circulation to the connective tissue where the inflammation process has begun. This leukocyte migration is done across the intercellular endothelial junctions and is affected by chemotactic peptide concentration gradient at the inflammatory focal point. At the inflammatory focal point, leukocytes become activated and start to secrete oxygen-reactive substances, pro-inflammatory cytokines, and lipid inflammatory mediators. They also excrete the contents of their granules. All these actions lead to a systemic inflammatory response by endocrine effects of pro-inflammatory cytokines and also cessation of the cause of the inflammation. However, in certain cases the amplification of the inflammation by pro-inflammatory cytokines is responsible of destruction of the tissue where it takes place [7]. The endocrine effects of pro-inflammatory cytokines are multiple; the principal effects are observed on the liver and the brain [8]. In the liver, they induce the synthesis of acute-phase proteins; on the brain, they result in fever, asthenia, anorexia, and somnolence (**Figure 2**).

#### **2.2 Inflammatory cytokines**

The term cytokine regroups the low-molecular-weight glycoproteins implicated in cellular communication. They are active in the control of proliferation, maturation, and differentiation of hematopoietic cells and also in the regulation of inflammatory and immunologic responses. They exercise their regulatory activity through an autocrine, paracrine, juxtacrine, and endocrine mechanism via the membrane receptors present on focus cells. In the field of immunology, there exist two groups of cytokines: pro-inflammatory cytokines such as interleukins 1, 6, 8, and 18 (IL-1, IL-6, IL-8, IL-18), TNFα and anti-inflammatory cytokines such as interleukins 10, 4, and 13 (IL-10, IL-4, IL-13) transforming growth factor β (TGFβ). The balance between pro-inflammatory and anti-inflammatory cytokines regulates the local intensity of an inflammatory reaction and its duration. Among pro-inflammatory cytokines, IL-1β and TNFα have the central role in the initiation and chronicity

#### **Figure 2.**

*Role of sentinel cells in the inflammatory response (modified from [8]). Sentinel cells (macrophage in this case) detects in its environment a potential danger by the pattern recognition receptors (PRR). This recognition active the inflammation signalization ways with the liberation of pro-inflammatory cytokines. PRRs considered in this example are toll like receptor 4 (TLR4) which recognize the lipo-poly-saccharide (LPS) of Gram negative bacteria and RAGE which recognize the ends products of glycation (AGEs).*

of inflammation. These cytokines are synthetized in an inactive precursor form: pro-IL-1β and pro-TNFα. Activation of pro-IL-1β is done by a cysteine/aspartatetype membrane protease named caspase-1 or IL-1β converting enzyme (ICE). Concerning TNFα, its liberation and activation require an adamalysine family enzyme called TNFα- converting enzyme (TACE). Interleukin-1β and TNFα have a synergetic action at the inflammation focal point; they are implicated in the expression of cyclooxygenase 2 (COX2); production of PGE2, NO, and PAF; expression of adhesion molecules at the endothelium level membrane; production of other proinflammatory cytokines; liberation of chemotactic peptides and metalloproteases; etc. The activities of these major pro-inflammatory cytokines are under the control of many natural inhibitors. These inhibitors can be classified regarding their mode of action into three categories:


Chemokines constitute another group of pro-inflammatory cytokines; they have chemotactic properties for the leukocytes. They are produced by all leukocytes, platelet, and connective tissue cells following stimulation by bacterial or viral products, IL-1β, TNFα, fragment C5a of complement, and leukotriene. Chemokine release leads to the degranulation and activation of leukocytes which provoke a massive release in the inflammatory focal point of lysosomal enzymes, oxidant, and lipid mediators [7].

**323**

*Neuroprotection: The Way of Anti-Inflammatory Agents DOI: http://dx.doi.org/10.5772/intechopen.90509*

immunosuppressing factors present in the CNS.

**2.3 Particularities of inflammation in the central nervous system**

In the central nervous system (CNS), the same inflammatory mechanism previously described remains valid. However, because of the blood–brain barrier, the actors and kinetic of inflammation in the CNS are particular [9]. Furthermore, in the CNS, the immune reactions are molded by the presence of cellular and molecular factors slowing the immune response [9]. In the physiologic conditions, the blood–brain barrier is not permeable to blood constitutes including immune cells. This immune isolation of the CNS brings up the question about the actors implicated in an inflammatory reaction in this particular organ. Many studies prove that the microglial cells located in the periventricular spaces express the class II molecules of the major histocompatibility complex (class II MHC) and can play the role of macrophages in the initiation and amplification of inflammation [9, 10]. Hence, microglial cells can be activated in CNS by three ways: pathogen-associated molecular patterns (PAMPs), missing self, or danger-associated molecular patterns (DAMPs) [11, 12]. This microglial cell activation leads to phagocytosis, antigen presentation, and production of pro-inflammatory cytokines [13]. Furthermore, the active microglial cells express the co-stimulant molecules including CD45, B7–1, B7–2, LFA-1, CD40, ICAM-1, and VCAM-1 which increase the permeability of the blood–brain barrier resulting in the penetration of immune cells in the CNS [9, 13]. It is possible for the active T lymphocytes to cross the blood–brain barrier and penetrate into the brain parenchyma [14]. If these infiltrated T lymphocytes recognize their specific antigen, they will produce pro-inflammatory cytokines that further increase the permeability of the blood–brain barrier [9]. However, this inflammatory activity caused by activated microglial cells or activated T lymphocyte in the CNS remains strongly modulated and inhibited by many cells and molecular

In the CNS, they are unappropriated conditions for the development and amplification of an inflammatory reaction. Indeed, we observe in the CNS a reduction of the expression of class I and class II molecules of the major histocompatibility complex on the cells, a local production of anti-inflammatory cytokines and a continuous elimination, by apoptosis, of the active T lymphocytes that have crossed the blood– brain barrier [9]. This apoptotic elimination of infiltrated T lymphocyte is the result of an interaction between receptors Fas/Apo-1 (CD95) on the active T lymphocytes and ligands FasL (CD95L) on the CNS cells [15, 16]. This "inflammo-resistance" state of the CNS is not necessarily an advantage. Indeed, low expression of class I molecules of the major histocompatibility complex on the CNS cells leads to two potential consequences. Firstly, it may be possible for the active immune cells if they cross the blood–brain barrier to attack the self CNS cells following the "missing self" principle [11]. Secondly, it may be difficult for active cytotoxic T lymphocyte when they cross the blood–brain barrier to destroy infected CNS cells in the case of CNS viral infection [17]. These consequences make the CNS particularly susceptible to persistent inflammatory states once the pathogen or other cause of inflammation has circumvented all the anti-inflammatory processes present in CNS [17]. Furthermore, even if apoptotic elimination of infiltrated active T lymphocytes leads to a modulation of inflammation in the CNS, it also delays the elimination of the cause of inflammation and therefore prolongs the inflammatory state in the CNS. Apoptosis of infiltrated active T lymphocytes also leads to the release, in the CNS parenchyma, of anti-inflammatory cytokines notably IL-10 and TGFβ which inhibit the cytotoxic activity of active T lymphocytes and thus might perpetuate an eventual CNS viral infection [18, 19]. It appears that it is difficult for an inflammatory process to begin in the CNS, but if for one reason or the other an inflammatory process does begin in

the CNS, it becomes very difficult to avert it completely and rapidly.

*Neuroprotection - New Approaches and Prospects*

of action into three categories:

**Figure 2.**

and TGFβ.

lipid mediators [7].

inflammatory cytokines on their receptors.

of inflammation. These cytokines are synthetized in an inactive precursor form: pro-IL-1β and pro-TNFα. Activation of pro-IL-1β is done by a cysteine/aspartatetype membrane protease named caspase-1 or IL-1β converting enzyme (ICE). Concerning TNFα, its liberation and activation require an adamalysine family enzyme called TNFα- converting enzyme (TACE). Interleukin-1β and TNFα have a synergetic action at the inflammation focal point; they are implicated in the expression of cyclooxygenase 2 (COX2); production of PGE2, NO, and PAF; expression of adhesion molecules at the endothelium level membrane; production of other proinflammatory cytokines; liberation of chemotactic peptides and metalloproteases; etc. The activities of these major pro-inflammatory cytokines are under the control of many natural inhibitors. These inhibitors can be classified regarding their mode

*negative bacteria and RAGE which recognize the ends products of glycation (AGEs).*

*Role of sentinel cells in the inflammatory response (modified from [8]). Sentinel cells (macrophage in this case) detects in its environment a potential danger by the pattern recognition receptors (PRR). This recognition active the inflammation signalization ways with the liberation of pro-inflammatory cytokines. PRRs considered in this example are toll like receptor 4 (TLR4) which recognize the lipo-poly-saccharide (LPS) of Gram* 

• The pro-inflammatory cytokine receptor antagonists: they compete with pro-

• The pro-inflammatory cytokine soluble receptors: they inhibit pro-inflammatory cytokine activities binding them; this family is represented by truncated

• The anti-inflammatory cytokines: they act by inhibition of pro-inflammatory cytokine biosynthesis; this family is represented by IL-4, IL-10, IL-11, IL-13,

Chemokines constitute another group of pro-inflammatory cytokines; they have

chemotactic properties for the leukocytes. They are produced by all leukocytes, platelet, and connective tissue cells following stimulation by bacterial or viral products, IL-1β, TNFα, fragment C5a of complement, and leukotriene. Chemokine release leads to the degranulation and activation of leukocytes which provoke a massive release in the inflammatory focal point of lysosomal enzymes, oxidant, and

receptors of IL-1β (IL-1 R1 and R2) and TNFα (TNF R55 and R75).

**322**
