**5.1 Blood-brain barrier and neurodegeneration**

The human brain comprises more than 600 km of blood vessels that guarantee oxygen, energy metabolites, and nutrients to brain cells and remove carbon dioxide and toxic metabolic products from the brain to the systemic circulation. A highly selective semipermeable border, called blood-brain barrier (BBB), separates the circulating blood from the central nervous system (CNS), regulating CNS homeostasis. Brain microvascular endothelia cells, neurons, astrocyte, pericytes, tight junctions, and basal membrane constitute tight brain capillaries in the BBB [160, 161]. It follows that BBB does not have fenestrations or other physical fissures for diffusion of small molecules. In fact, ions, solutes, and hormones can pass the BBB by passive diffusion through the paracellular pathway between adjacent cells. Hydrophilic biomolecules (i.e., proteins and peptides) can cross the BBB within specific and saturable receptor-mediated transport mechanisms [162]. The components of BBB constantly adapt in response to various physiological and pathological modifications into the brain [163, 164]. Loss of BBB integrity is correlated with vascular permeability increase, cerebral blood flow impairs, and hemodynamic response alteration [165]. In neurodegenerative disorders, endothelia degeneration leads to loss of tight junctions [166, 167], brain capillary leakages [168, 169], pericyte degeneration [170], endothelial cell remodeling [164], cellular infiltration [171, 172], and aberrant angiogenesis [173, 174]. All these BBB disruptions let different blood proteins (i.e., fibrinogen, plasminogen, and thrombin), water, and electrolytes to accumulate in different zones of CNS, enhancing the on progress of PD and AD [165]. Consequently, to project effective drugs for neurodegeneration, it is necessary to understand in detail BBB pathological aberrations.

Due to their safeness and tolerance [175–177], polyphenols are currently studied as neuroprotectors. It is important to point out that for exerting their action, polyphenols must accumulate in the brain in an active form and in sufficient concentration. The limiting step is choosing the right administration route. In most of the clinical studies, the oral administration is the preferred way, but recently the nasal delivery is taken into consideration for the easiness to bypass the BBB [178], the increased bioavailability, the decreased metabolism, and peripheral side effects [179, 180]. The major problem of oral administration relies on poor absorbance of the modified form of polyphenols (i.e., glycosides and ester polymers) in the upper portion of the gut leading to the passage in the colon in which polyphenols are converted by gut-microbiota in the aglycone form or other substances able to be better absorbed [181, 182]. Once absorbed, they can be further modified by enzymes and eliminated [183, 184] or adsorbed to plasmatic proteins (i.e., albumin) and then accumulated in different districts [185].
