**4. Barriers that restrict the entry of substances into the brain**

#### **4.1 Blood: Brain barrier (BBB)**

The blood-brain barrier (BBB) is a term used to describe the unique properties of the microvasculature of the central nervous system (CNS). CNS is made of continuous and non-fenestrated vessels. These blood vessels function to regulate the movement of molecules, ions, and cells between the blood and the CNS [28, 29]. The central nervous system of vertebrates is isolated from the rest of the body by BBB. Normal functioning of BBB is essential for homeostasis. The BBB is made of two main types of cells, that is, endothelial cells (EC) and mural cells. ECs function to regulate the movement of ions, molecules, and cells between the blood and the brain. ECs are held together by tight junctions (TJs), which greatly restrict the paracellular movement of solutes [30]. The tight junctions hold CNS ECs in place forming a paracellular barrier to molecules and ions [30].

Mural cells are the cells surrounding the large vessels and pericytes, which are present on the abluminal surface of the endothelium [31]. Pericytes and astrocytes are considered the key cell types involved in BBB regulation through their interactions with brain endothelial cells. Astrocytes interact with brain endothelium and are thought to be involved in the maintenance of BBB endothelial cell properties [32] and regulate BBB permeability [33]. The BBB restricts the movement of molecules by forming a physical barrier, which is represented by tight junctions between the endothelial cells. The endothelial cells express two main types of transporters: the efflux transporters, which transport lipophilic substances toward the blood [34] and nutrient transporters, which transport nutrients into the CNS and remove waste products from the CNS to the blood [35]. The EC cells of the CNS are characterized by a higher number of mitochondria [36]. These mitochondria supply the BBB with Adenosine triphosphate to carry out their transport processes.

Other cell types of the BBB are astrocytes and immune cells, mainly macrophages and microglial cells [30]. Pericytes, astrocyte end-feet, and a discontinuous basal membrane support the functions of the BBB. The highly selective functionality of the BBB is due to endothelial tight junctions that are assisted by astrocytes and pericytes. The tight influx control is complemented by the efflux transport system, which rapidly eliminates classic xenobiotics and NMs buildup in the brain [37]. However, nanomaterials have been reported to cross the BBB via a transcytosis-mediated route [38].

#### **4.2 Metabolic barrier**

A second barrier observed in the nervous system is the metabolic barrier. The metabolic barrier is composed of enzymes and transport systems [39]. The metabolism of endothelial cells plays an important role in the function of BBB. L-Dihydroxyphenylalanine is the precursor of dopamine which enters the brain through the neutral amino acid-transport system. However, its entry is restricted due to L-Dihydroxyphenylalanine decarboxylase and monoamine oxidase inside the endothelial cells of the brain capillaries. This "enzymatic blood-brain barrier" limits the passage of L-Dihydroxyphenylalanine into the brain (https://nba.uth.tmc. edu/neuroscience/m/s4/chapter11.html). The brain capillaries contain enzymes that metabolize neurotransmitters. These enzymes include endopeptidases, cholinesterases, aminopeptidases, and Gamma-Aminobutyric acidtransaminases. The brain capillaries also contain drug and toxin-metabolizing enzymes found in the liver [40].

The endothelium of the BBB lacks pinocytic vesicles. This limits pinocytosis by the cells of BBB. The cells of BBB express many enzymes on the intra and

*In-Utero Neurotoxicity of Nanoparticles DOI: http://dx.doi.org/10.5772/intechopen.101452*

extracellular surfaces, which restrict the movement of substances through the BBB. P-glycoproteins, and similar substances present on the endothelial cells also help to eliminate various endogenous and exogenous toxins [18]. P-glycoproteins cause multi-drug-resistant cancer cells to pump out the drugs. The endothelial cells have P-proteins, which help to pump some hydrophobic substances like cyclosporin A, domperidone, digoxin and so on into the blood.
