## 4 The Blood-Brain-Barrier  
On average, the adult human brain accounts for about 2% of body weight. Despite its relatively small size, it consumes about 20% of glucose-derived energy [40]. Indeed, the mammalian brain depend upon glucose as its main source of energy. Furthermore, neurons within the CNS have a high energy demand, requiring a continuous supply of energy substrates (mainly glucose) and nutrients from the blood [41]. Moreover, neurons communicate using several chemical (ions, neurotransmitters, neuromodulators and neuropeptides) and electrical signals (synaptic and action potentials). Therefore, an accurate regulation of the axons and synaptic ionic microenvironments is \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Drug** & **Donepezil** & **Rivastigmine** & **Galantamine** & **Mementine** \\  & **(Aricept®, 1996)** & **(Exelon®, 2000)** & **(Razadyne®, 2001)** & **(Ebix®, 2003)** \\ \hline
**Pharmaceutical company** & Pfizer, New York, USA &
\begin{tabular}{c} Novartis, Basel, \\ Switzerland \\ \end{tabular} & Janssen, New Jersey, USA & Lundbeck, Valby, Denmark \\ \hline
**Class and indication** & \begin{tabular}{c} AChE inhibitor prescribed \\ to treat symptoms of \\ mild-to-moderate and \\ moderate-to-severe AD \\ \end{tabular} & AChE inhibitor prescribed & \begin{tabular}{c} NMDA receptor \\ to treat symptoms of \\ mild-to-moderate AD \\ \end{tabular} & \
\begin{tabular}{c} NMDA receptor \\ antagonist prescribed to \\ mild-to-moderate AD \\ \end{tabular} &
\begin{tabular}{c} N-t antagonist \\ treat symptoms of \\ moderate-to-severe AD \\ \end{tabular} \\ \hline
**Mechanism of action** & \begin{tabular}{c} Prevents the breakdown \\ of ACh in the brain \\ \end{tabular} & \begin{tabular}{c} Prevents the breakdown \\ of ACh and butyrylcholine \\ in the brain \\ \end{tabular} & \
\begin{tabular}{c} Prevents the breakdown \\ of ACh and stimulates \\ nicotinic receptors to \\ release more ACh in \\ the brain \\ \end{tabular} &
\begin{tabular}{c} Blocks the toxic effects \\ associated with excess \\ glutamate and regulates \\ glutamate activation \\ \end{tabular} \\ \hline
**Common adverse effects** & \begin{tabular}{c} Nausea (3–19\%), vomiting \\ (3–9\%), diarrhea (5–15\%) \\ \end{tabular} & \begin{tabular}{c} Nausea (17–47\%), \\ diarrhea (5–19\%), loss of \\ appetite (\(\geq\)17\%), weight \\ loss (3–26\%), muscle \\ \end{tabular} & \
\begin{tabular}{c} Nausea (21\%), vomiting \\ diarrhea (7\%), loss \\ appetite (\(\geq\)17\%), weight \\ weight loss (3–5\%), \\ \end{tabular} &
\begin{tabular}{c} Dizziness (5–7\%), \\ headache (6\%), \\ constipation (3–5\%), \\ confusion \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: FDA-approved drugs for AD (based on [39]). critical for healthy brain physiology [42]; thus, reliable neural signaling is governed by the barrier layers existing between blood and neural tissue [43]. The adult brain is composed of two main interfacial barriers, namely: (i) the blood-cerebrospinal fluid barrier, which is composed of epithelial cells of the choroid plexus facing the cerebrospinal fluid [42] and (ii) the avascular aranchoid epithelium, underlying dura and enclosing CNS, also forms a barrier layer, even though its avascular nature and small surface area do not promote a significant surface extension for exchange between the blood and the CNS [44]. Besides these two barriers, the BBB represents the largest interface for blood-brain exchange, and is created by the endothelial cells that form the walls of the capillaries [42]. As a result, there is a direct interaction with the circulating blood, making the BBB the most selective physical barrier and allowing it to exert the tightest control over the immediate microenvironment of brain cells [45]. In fact, the BBB is present in all organisms with a well-developed CNS [46], and is responsible for ensuring the proper environment for neuronal network functionality and brain homeostasis.