**2. Blood brain barrier**

One unique feature about the blood vessels in the brain is the presence of the blood-brain barrier (BBB). BBB is a natural barrier that separates the central nervous system (CNS) from the circulation [1]. Under physiological conditions, the BBB prevents the entrance of blood cells and large molecules into the brain, but allows the uptake of nutrients and hormones from the blood, maintaining the homeostasis of CNS microenvironment [1, 2]. Under pathological conditions, the integrity of BBB is compromised and blood components leak into the brain, contributing to the progress of diseases [3-12]. At the cellular level, the BBB consists of brain

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microvascular endothelial cells (BMECs), astrocytes, pericytes, neurons, microglia, and the non-cellular component-basement membrane [13] (Figure 1).

transports glucose; monocarboxylate transporter 1 (MCT1) transports lactate; the L1 and y +transporters transport large neutral and cationic essential amino acids to and from the brain. Group II transporters are also expressed on both sides of BMECs, but only transport materials in one direction [27-29]. For example, transferrin and insulin receptors (TFR and IR) are expressed on both sides of BMECs. The luminal and abluminal receptors mediate endocytosis of transferrin and insulin from the blood and brain, respectively. Group III transporters are expressed on only one side of BMECs and usually mediate one-way transportation of materials [26, 30-38]. For instance, in order to remove excitatory neurotransmitter glutamate from the brain, excitatory amino acid transporters (EAATs) are exclusively expressed on the abluminal side of BMECs. Similarly, to facilitate the removal of amyloid-β from the brain, low-density lipoprotein receptor related protein 1 (LRP1) is solely expressed on the abluminal side of

abluminal side to regulate ion homeostasis and thus proper neuronal & synaptic functions. Additionally, multidrug resistance related protein 1 (MRP1) and P-glycoprotein (P-gp) are primarily expressed on BMEC luminal side to efflux many types of drugs from the brain. The subcellular distribution of these transporters and receptors is summarized in Figure 2.

**Figure 2.** Major transporters and receptors expressed by BMECs. Three groups of transporters are expressed in BMECs. Group I includes GLUT1, MCT1, L1 and y+transporters, which are expressed on both luminal and abluminal sides of BMECs and transport materials bi-directionally. Group II includes TRP and IR, which are expressed on both sides of BMRCs but transport materials in one direction. Group III includes EAATs, LRP1, (Na+-K+)ATPase, MRP1 and P-gp, wich


) ATPase, which is only found on the

Recovery from ICH – Potential Targets http://dx.doi.org/10.5772/58477 91

BMECs. Another example of such transporters is (Na+

are expressed on only one side of BMECs.

**Figure 1.** Schematic illustration of BBB. The BBB is composed of cellular and non-cellular components. Cellular compo‐ nents include BMECs, perycites, astrocytic endfeet, neurons, and microglia. Non-cellular components includes the basement membrane.

#### **a.** BMECs

Endothelial cells in the CNS, BMECs, are different in many ways from the ones in the periphery. First, BMECs have more mitochondria, lower pinocytotic activity, and little-to-no fenestra‐ tions. Second, the endothelium in the brain and the spinal cord is 50-100 times tighter than that in the rest of the body [14]. In the CNS, BMECs connect to each other via tight junctions, which are unique structures that confer impermeability to the BBB. Two types of proteins are found at tight junctions: transmembrane proteins, including occludin and claudins, and cytoplasmic accessory proteins, including zonula occluden-1, 2, 3 (ZO-1, 2, 3) and cingulin [15, 16]. The transmembrane proteins seal gaps between adjacent cells, decreasing intercellular permeabil‐ ity [17, 18], whereas cytoplasmic accessory proteins link transmembrane proteins to cortical actin-based cytoskeleton, enabling strict regulation of the distribution of tight junction proteins (TJP) [19, 20].

Besides intercellular transportation, intracellular transportation is another way to regulate BBB permeability [11, 21-23]. Although small lipophilic molecules, such as oxygen and carbon dioxide, can diffuse across BMECs freely [24], the transport of large hydrophilic molecules is mediated by specific transporters or receptors. Based on their subcellular distribution and functions, these transporters and receptors are divided into three groups. Group I transporters are expressed on both luminal and abluminal sides of BMECs and function to transport nutrients between the blood and brain [25, 26]. For example, glucose transporter 1 (GLUT1) transports glucose; monocarboxylate transporter 1 (MCT1) transports lactate; the L1 and y +transporters transport large neutral and cationic essential amino acids to and from the brain. Group II transporters are also expressed on both sides of BMECs, but only transport materials in one direction [27-29]. For example, transferrin and insulin receptors (TFR and IR) are expressed on both sides of BMECs. The luminal and abluminal receptors mediate endocytosis of transferrin and insulin from the blood and brain, respectively. Group III transporters are expressed on only one side of BMECs and usually mediate one-way transportation of materials [26, 30-38]. For instance, in order to remove excitatory neurotransmitter glutamate from the brain, excitatory amino acid transporters (EAATs) are exclusively expressed on the abluminal side of BMECs. Similarly, to facilitate the removal of amyloid-β from the brain, low-density lipoprotein receptor related protein 1 (LRP1) is solely expressed on the abluminal side of BMECs. Another example of such transporters is (Na+ -K+ ) ATPase, which is only found on the abluminal side to regulate ion homeostasis and thus proper neuronal & synaptic functions. Additionally, multidrug resistance related protein 1 (MRP1) and P-glycoprotein (P-gp) are primarily expressed on BMEC luminal side to efflux many types of drugs from the brain. The subcellular distribution of these transporters and receptors is summarized in Figure 2.

microvascular endothelial cells (BMECs), astrocytes, pericytes, neurons, microglia, and the

**Figure 1.** Schematic illustration of BBB. The BBB is composed of cellular and non-cellular components. Cellular compo‐ nents include BMECs, perycites, astrocytic endfeet, neurons, and microglia. Non-cellular components includes the

Endothelial cells in the CNS, BMECs, are different in many ways from the ones in the periphery. First, BMECs have more mitochondria, lower pinocytotic activity, and little-to-no fenestra‐ tions. Second, the endothelium in the brain and the spinal cord is 50-100 times tighter than that in the rest of the body [14]. In the CNS, BMECs connect to each other via tight junctions, which are unique structures that confer impermeability to the BBB. Two types of proteins are found at tight junctions: transmembrane proteins, including occludin and claudins, and cytoplasmic accessory proteins, including zonula occluden-1, 2, 3 (ZO-1, 2, 3) and cingulin [15, 16]. The transmembrane proteins seal gaps between adjacent cells, decreasing intercellular permeabil‐ ity [17, 18], whereas cytoplasmic accessory proteins link transmembrane proteins to cortical actin-based cytoskeleton, enabling strict regulation of the distribution of tight junction proteins

Besides intercellular transportation, intracellular transportation is another way to regulate BBB permeability [11, 21-23]. Although small lipophilic molecules, such as oxygen and carbon dioxide, can diffuse across BMECs freely [24], the transport of large hydrophilic molecules is mediated by specific transporters or receptors. Based on their subcellular distribution and functions, these transporters and receptors are divided into three groups. Group I transporters are expressed on both luminal and abluminal sides of BMECs and function to transport nutrients between the blood and brain [25, 26]. For example, glucose transporter 1 (GLUT1)

non-cellular component-basement membrane [13] (Figure 1).

basement membrane.

90 Intracerebral Hemorrhage

**a.** BMECs

(TJP) [19, 20].

**Figure 2.** Major transporters and receptors expressed by BMECs. Three groups of transporters are expressed in BMECs. Group I includes GLUT1, MCT1, L1 and y+transporters, which are expressed on both luminal and abluminal sides of BMECs and transport materials bi-directionally. Group II includes TRP and IR, which are expressed on both sides of BMRCs but transport materials in one direction. Group III includes EAATs, LRP1, (Na+-K+)ATPase, MRP1 and P-gp, wich are expressed on only one side of BMECs.

#### **b.** Astrocytes

More than 30 years ago Stewart and Wiley, using xenograft experiments, demonstrated that the unique properties of BMECs, including increased mitochondria number, few pinocytotic vesicles and presence of tight junctions [39], were induced by the microenvironment of the CNS. Astrocytes, which constitute the major glial cells in the brain that cover more than 99% of the vascular surface using their extended endfeet [40, 41], have been suggested to contribute to these unique features of BMECs as well as the impermeability of BBB. Consistent with this hypothesis, temporary focal loss of astrocytes positively correlates with the compromise of BBB integrity *in vivo* [42]*.* Additionally, injected astrocytes have been shown to cover the blood vessels in the eye and prevent the leakage of Evans blue from the circulation system [43]. Moreover, *in vitro* culture experiments revealed that BMEC-astrocyte co-culture had a higher transendothelial electrical resistance (TEER) and less leakage of tracers, compared to BMEC monolayer [44-46]. Further mechanistic studies have demonstrated that both direct contact and astrocyte-secreted soluble factors, such as Ang1, TGF-β, GDNF and FGF2, are responsible for the impermeability of BBB [47-49]. These data suggest that astrocytes, by interacting with BMECs directly and indirectly, contribute to the unique properties of BMECs and the imper‐ meability of BBB. Therefore, the co-culture of BMEC with astrocytes has been one of the most widely used *in vitro* BBB models, since it replicates in a petri dish the tight structures observed *in vivo*.

Mechanistic studies demonstrate that BBB breakdown in pericyte-deficient mice is due to diminished expression of BBB-specific genes in endothelial cells and lack of polarity in astrocytic endfeet [58]. Consistent with these data, adding pericytes to BMEC-astrocyte coculture system significantly enhanced TEER and decreased the leakage of tracers [61, 62]. Further studies showed that the function of pericytes on BBB integrity is also dependent on the differentiation stage of pericytes [63]. TGF-β treated pericytes, which are further differen‐

these data suggest that pericytes is a key regulator of the BBB integrity. Nowadays, BMEC-

In the human brain, the number of neurons and capillaries is estimated to be the same [64]. Both BMECs and astrocytic processes are directly innervated by noradrenergic, serotonergic, cholinergic, and GABA-ergic neurons [65-71]. The fact that local neuronal activity and metabolism regulate cerebral blood flow (neurovascular coupling) suggests that neurons may regulate BBB permeability through modulating BMEC and astrocyte function [72]. Consistent with these data, adding neurons to *in vitro* BBB models significantly increases the tightness of the BBB [73]. However, the exact mechanism underlying how neurons contribute to the BBB

Microglia, the brain resident immune competent cells, account for 10-20% of glial cells in the brain [74, 75]. Fate mapping studies suggest that they originate from Myb-independent, FLT3 independent, but PU.1-dependent myeloid progenitors that express colony stimulating factor 1 receptor (Csf1R) at embryonic day 8.5 [76-80]. Under physiological conditions, microglia have a ramified morphology, characterized by a small cell body and many long/thin dynamic processes [75]. By extending and retracting these dynamic processes, microglia survey the changes of microenvironment in the brain [75]. Once an insult is identified, microglia quickly undergo a process collectively termed activation, which involves changes to ameboid mor‐ phology. Activated microglia migrate to the site of injury, proliferate locally, secrete pro-and anti-inflammatory cytokines, and remove cellular debris by phagocytosis [74, 81-83]. Microglia play a dual role in the brain. On one hand, they contribute to neurite growth and neuronal survival by clearing cell debris and releasing neurotrophic factors [84-86], such as neurotro‐ phin-3 and brain-derived neurotrophic factor. On the other hand, microglia secrete high levels of pro-inflammatory cytokines, including TNF-α and IL-1β, promoting neuronal death. The former (neuroprotective microglia) display anti-inflammatory properties and are called M2 cells, similar to the nomenclature of macrophages. The latter, secreting pro-inflammatory cytokines, exhibit neurotoxic behaviors and are called M1 microglia. Which role they play is highly dependent on the timing after injury and the type of injury. Since microglia are close to other components of the BBB in the brain, they may regulate BBB integrity either by directly interacting with the blood vessels, or indirectly through interaction with BMECs, astrocyte endfeet, or pericytes [87]. Interestingly, microglial activation has been reported to both

pericyte-astrocyte triple-culture is becoming more and more popular in BBB research.

integrity is still elusive. Many studies focus on such mechanisms.

pericytes, compromise BBB integrity. On the contrary, b-FGF treated pericytes,

pericytes, maintain impermeability of BBB. Altogether,

Recovery from ICH – Potential Targets http://dx.doi.org/10.5772/58477 93

tiated SMA+

**d.** Neurons

**e.** Microglia

which are less differentiated SMA-

#### **c.** Pericytes

Discovered in 1873, pericytes are perivascular cells sandwiched between endothelial cells and astrocytic endfeet [50]. They are embedded in the basement membrane under normal condi‐ tions [1]. Pericytes cover capillaries and the degree of coverage varies depending on the species and tissue type[51]. It has been shown that the pericyte-to-endothelial ratio is 1:5 in rats, 1:4 in mice, and 1:3-4 in humans [52, 53]. In mice, this ratio is 1:1 in retina, 1:3 in brain and 1:100 in skeletal muscle vasculature [54], representing how tightly the blood vessels and their contents are confined in different tissues. Pericytes have several different developmental origins, depending on the organs they cover [51]. In the brain and thymus, pericytes arise from ectoderm-derived neural crest, whereas they differentiate from the mesothelium in the lungs, liver, and gut [51]. So far, there are no pericyte-specific markers available [51], although many cellular markers, including α-smooth muscle actin (SMA), PDGFRβ, Desmin, CD13, NG2, and RGS-5, have been used to identify pericytes, primarily in combination, as none of these markers is exclusive for these cells (pericytes share markers with myofibroblasts, vascular smooth muscle cells and neuronal progenitors [51]). It should be noted that the expression of these markers is high dependent on the differentiation stage of pericytes.

The main functions of pericytes include BBB regulation, vascular development and injury repair [52, 55, 56]. Here we focus on BBB regulation. It has been shown that pericyte-deficient mice have compromised BBB and pericyte coverage positively correlates with the tightness of tight junction [11, 57, 58]. Additionally, pericytes migrate away from capillaries, decreasing their coverage, under pathological conditions, such as hypoxia and traumatic brain injury [59, 60]. These data suggest that pericytes play a critical role in BBB integrity and maintenance. Mechanistic studies demonstrate that BBB breakdown in pericyte-deficient mice is due to diminished expression of BBB-specific genes in endothelial cells and lack of polarity in astrocytic endfeet [58]. Consistent with these data, adding pericytes to BMEC-astrocyte coculture system significantly enhanced TEER and decreased the leakage of tracers [61, 62]. Further studies showed that the function of pericytes on BBB integrity is also dependent on the differentiation stage of pericytes [63]. TGF-β treated pericytes, which are further differen‐ tiated SMA+ pericytes, compromise BBB integrity. On the contrary, b-FGF treated pericytes, which are less differentiated SMApericytes, maintain impermeability of BBB. Altogether, these data suggest that pericytes is a key regulator of the BBB integrity. Nowadays, BMECpericyte-astrocyte triple-culture is becoming more and more popular in BBB research.

#### **d.** Neurons

**b.** Astrocytes

92 Intracerebral Hemorrhage

*in vivo*.

**c.** Pericytes

More than 30 years ago Stewart and Wiley, using xenograft experiments, demonstrated that the unique properties of BMECs, including increased mitochondria number, few pinocytotic vesicles and presence of tight junctions [39], were induced by the microenvironment of the CNS. Astrocytes, which constitute the major glial cells in the brain that cover more than 99% of the vascular surface using their extended endfeet [40, 41], have been suggested to contribute to these unique features of BMECs as well as the impermeability of BBB. Consistent with this hypothesis, temporary focal loss of astrocytes positively correlates with the compromise of BBB integrity *in vivo* [42]*.* Additionally, injected astrocytes have been shown to cover the blood vessels in the eye and prevent the leakage of Evans blue from the circulation system [43]. Moreover, *in vitro* culture experiments revealed that BMEC-astrocyte co-culture had a higher transendothelial electrical resistance (TEER) and less leakage of tracers, compared to BMEC monolayer [44-46]. Further mechanistic studies have demonstrated that both direct contact and astrocyte-secreted soluble factors, such as Ang1, TGF-β, GDNF and FGF2, are responsible for the impermeability of BBB [47-49]. These data suggest that astrocytes, by interacting with BMECs directly and indirectly, contribute to the unique properties of BMECs and the imper‐ meability of BBB. Therefore, the co-culture of BMEC with astrocytes has been one of the most widely used *in vitro* BBB models, since it replicates in a petri dish the tight structures observed

Discovered in 1873, pericytes are perivascular cells sandwiched between endothelial cells and astrocytic endfeet [50]. They are embedded in the basement membrane under normal condi‐ tions [1]. Pericytes cover capillaries and the degree of coverage varies depending on the species and tissue type[51]. It has been shown that the pericyte-to-endothelial ratio is 1:5 in rats, 1:4 in mice, and 1:3-4 in humans [52, 53]. In mice, this ratio is 1:1 in retina, 1:3 in brain and 1:100 in skeletal muscle vasculature [54], representing how tightly the blood vessels and their contents are confined in different tissues. Pericytes have several different developmental origins, depending on the organs they cover [51]. In the brain and thymus, pericytes arise from ectoderm-derived neural crest, whereas they differentiate from the mesothelium in the lungs, liver, and gut [51]. So far, there are no pericyte-specific markers available [51], although many cellular markers, including α-smooth muscle actin (SMA), PDGFRβ, Desmin, CD13, NG2, and RGS-5, have been used to identify pericytes, primarily in combination, as none of these markers is exclusive for these cells (pericytes share markers with myofibroblasts, vascular smooth muscle cells and neuronal progenitors [51]). It should be noted that the expression of these

The main functions of pericytes include BBB regulation, vascular development and injury repair [52, 55, 56]. Here we focus on BBB regulation. It has been shown that pericyte-deficient mice have compromised BBB and pericyte coverage positively correlates with the tightness of tight junction [11, 57, 58]. Additionally, pericytes migrate away from capillaries, decreasing their coverage, under pathological conditions, such as hypoxia and traumatic brain injury [59, 60]. These data suggest that pericytes play a critical role in BBB integrity and maintenance.

markers is high dependent on the differentiation stage of pericytes.

In the human brain, the number of neurons and capillaries is estimated to be the same [64]. Both BMECs and astrocytic processes are directly innervated by noradrenergic, serotonergic, cholinergic, and GABA-ergic neurons [65-71]. The fact that local neuronal activity and metabolism regulate cerebral blood flow (neurovascular coupling) suggests that neurons may regulate BBB permeability through modulating BMEC and astrocyte function [72]. Consistent with these data, adding neurons to *in vitro* BBB models significantly increases the tightness of the BBB [73]. However, the exact mechanism underlying how neurons contribute to the BBB integrity is still elusive. Many studies focus on such mechanisms.

#### **e.** Microglia

Microglia, the brain resident immune competent cells, account for 10-20% of glial cells in the brain [74, 75]. Fate mapping studies suggest that they originate from Myb-independent, FLT3 independent, but PU.1-dependent myeloid progenitors that express colony stimulating factor 1 receptor (Csf1R) at embryonic day 8.5 [76-80]. Under physiological conditions, microglia have a ramified morphology, characterized by a small cell body and many long/thin dynamic processes [75]. By extending and retracting these dynamic processes, microglia survey the changes of microenvironment in the brain [75]. Once an insult is identified, microglia quickly undergo a process collectively termed activation, which involves changes to ameboid mor‐ phology. Activated microglia migrate to the site of injury, proliferate locally, secrete pro-and anti-inflammatory cytokines, and remove cellular debris by phagocytosis [74, 81-83]. Microglia play a dual role in the brain. On one hand, they contribute to neurite growth and neuronal survival by clearing cell debris and releasing neurotrophic factors [84-86], such as neurotro‐ phin-3 and brain-derived neurotrophic factor. On the other hand, microglia secrete high levels of pro-inflammatory cytokines, including TNF-α and IL-1β, promoting neuronal death. The former (neuroprotective microglia) display anti-inflammatory properties and are called M2 cells, similar to the nomenclature of macrophages. The latter, secreting pro-inflammatory cytokines, exhibit neurotoxic behaviors and are called M1 microglia. Which role they play is highly dependent on the timing after injury and the type of injury. Since microglia are close to other components of the BBB in the brain, they may regulate BBB integrity either by directly interacting with the blood vessels, or indirectly through interaction with BMECs, astrocyte endfeet, or pericytes [87]. Interestingly, microglial activation has been reported to both compromise and restore BBB integrity [88, 89]. This discrepancy could be explained by different injury models and different timing after injury. More work is needed to answer the question how microglia regulate BBB integrity.

disrupted BBB, peripheral leukocytes infiltrate into the brain. The infiltrated leukocytes together with activated microglia produce more pro-inflammatory mediators, which induce cell death in the penumbra area [107, 108]. In addition, hemolysis of red blood cells causes iron deposition in the brain parenchyma and subsequent lipid peroxidation [109]. Free radicals generated during lipid peroxidation also lead to cell death and contribute to ICH-induced brain injury [110, 111]. With the progress of disease, microglia and infiltrated leukocytes change their gene expression profile from pro-inflammatory to anti-inflammatory and clear up the dead cells via phagocytosis [110, 112]. The clearance of cell debris finally leads to the resolution of the hematoma and repair of damaged tissue. At this stage, the activated inflam‐ matory cells revert to a resting state again. Due to the limited regenerative ability of neurons, however, most neurological functions cannot be recovered, which explains the high extent of

Recovery from ICH – Potential Targets http://dx.doi.org/10.5772/58477 95

To study ICH and eventually cure this disease, several ICH animal models have been devel‐ oped, including collagenase ICH model, whole blood ICH model, and the spontaneous ICH model. Although these models have been widely used in ICH research, none of them fully replicates the pathology of ICH in human patients. Here we briefly discuss the advantages

This model utilizes the enzymatic activity of collagenase, a bacterial enzyme. After injection into the brain, collagenase induces rupture of blood vessels by degrading collagen IV, a component of the blood vessel wall [103-105]. The rupture of blood vessels then induces the formation of hematoma and other pathological alterations. There are many advantages of this model. First, ICH induced by collagenase injection is very reliable and reproducible. The size and location of hematoma reported by different laboratories across the world are comparable [112-115]. Second, the location of hematoma can be controlled depending on the site of injection. Third, this model is very simple and fast. ICH can be induced within hours after collagenase injection. Due to these advantages, collagenase ICH model has become one of the most popular animal models for ICH research. This model, however, also has a few disad‐ vantages. One of the most significant drawbacks is that it introduces collagenase, a bacterial enzyme, into the mammalian brain. This enzyme degrades ECM proteins in the brain, affects BBB integrity, and modifies inflammatory or immune responses, all of which may affect ICH progress [105, 116, 117]. Another disadvantage of this model is that it does not replicate the vascular challenges usually seen before the onset of ICH in patients, such as hypertension and atherosclerosis. Mice lacking these vascular injuries may have different disease progress and/ or recovery patterns, which makes it difficult to interpret data generated using this ICH model.

disability after ICH.

**4. ICH animal models**

and disadvantages of these models.

**a.** Collagenase ICH Model

**b.** Whole Blood ICH Model

**f.** Basement Membrane (BM)

BM is a 3-dimensional network composed of extracellular matrix (ECM) proteins, including collagens, laminins, heparin sulfate proteoglycans, and nidogens [47, 90]. The formation of this network involves polymerization and cross-link of these ECM proteins [90, 91]. At the BBB, BMECs generate a vascular BM and astrocytes generate a parenchymal BM [92, 93]. The vascular and parenchymal BM is usually indistinguishable at capillaries [1]. However, at the post-capillary venules, the two BMs are separated by perivascular space where cerebrospinal fluid drains, and where antigen-presenting cells can be found [1]. Both BM layers have the same composition except that in the vascular BM laminin-α4 and-α5 are predominantly present [93], whereas in the parenchymal BM laminins-α1 and-α2 are the main components [92-94].

Accumulating evidence suggests that loss of BM results in disruption of BBB, probably due to the loss of a physical barrier at the BMEC-astrocyte interface and/or lack of signaling from ECM molecules [95-99]. Individual ECM proteins, including laminin, collagen type IV, and fibronectin, have been shown to increase the TEER of BMECs *in vitro* [100]. Using laminin conditional knockout mice, we have shown that astrocytic laminin maintains BBB integrity by preventing pericyte differentiation from the resting stage to the contractile stage [101]. In addition, laminin α5 and dystroglycan, a major receptor for ECM proteins, have been found to negatively correlate with the infiltration of leukocytes in the brain [93]. These data suggest that BM plays a crucial role in BBB regulation. Future studies are expected to focus on the roles of individual ECM proteins in BBB integrity. Understanding how these ECM proteins affect individual BBB components and BBB integrity would significantly enhance our knowledge on BBB and potentially pave the way for the treatment of many neurological disorders.
