Traditional Views Of The Cp

Production of CSF

The most recognized function of the CP is CSF production (13). CSF formation across species is generally proportional to the weight of the CP. In humans, CSF volume is 80-150 mL and forms at a rate of approx 500 mL per d. CSF production follows a circadian rhythm, with nighttime levels (0200 hours) doubling the levels produced during the daytime (14). As much as 30% of the CSF is formed at other sites, particularly under pathological conditions, including the ependymal lining of the ventricles and the endothelium of brain capillaries.

Secretion and Composition

CSF is produced mainly by active secretion; water enters the CSF from the blood along an osmotic gradient or by specific water channels (e.g., aquaporin). The epithelial cells of the CP secrete CSF by moving Na(+), Cl(-), and HCO3(-) from the blood to the ventricles, creating a gradient that drives the secretion of H2O. The CSF is clear, with few cells and little protein (15). Compared to blood plasma, CSF has a lower pH and concentrations of glucose, potassium, calcium, bicarbonate, and amino acids (16,17). In contrast, sodium, chloride, and magnesium contents are greater in CSF than in blood plasma. Folate levels are two to three times higher in CSF than in plasma, and transthyretin (TTR) represents 25% of all CSF proteins (18,19). Interestingly, TTR is produced exclusively by the CP. Notably, a link has been described between TTR and depression. Studies in both TTR-null mice and depressed patients suggest a relationship between lowered TTR and increased exploratory behavior and increased Hamilton depression scores.

Circulation and Absorption

CSF in the subarachnoid space flows from the lateral foramin of Lushka and the cisterna pontis, anteriorly along the base of the brain through the Sylvian fissure, and along the lateral convex and medial surfaces of the hemispheres. From the midline foramen of Magendie and cisterna magna, the CSF flows over the cerebellar hemispheres toward the tentorial incisure and downward into the subarachnoid space that surrounds the spinal cord. The circulation of CSF involves pressure waves generated by pulsatile arterial blood flow and brain expansion, pressure gradients created by the production and absorption of CSF, and currents induced by ependymal cilia (20).

CSF accesses the blood primarily through the arachnoid villi, which are continuous with the subarachnoid space. Because the hydrostatic pressure of CSF exceeds the venous pressure, the villi act as one-way valves that return CSF from the subarachnoid space to the dural venous sinuses. Small amounts of CSF are absorbed via pial vessels, across capillary walls, and via lymphatic channels adjacent to extensions of the subarachnoid space surrounding cranial and spinal nerves. These routes of absorption are particularly important under pathological conditions, such as hydrocephalus (21).

Formation of the CSF-Blood Barrier

The typical function of the blood-brain barrier (BBB) within the CP is shifted from the vasculature to the epithelium, where tight junctions form between the epithelial cells to confer the permeability properties of the individual cells (22). Briefly, the CP and arachnoid membrane act together at the barriers between blood and CSF. On the external brain surface, the ependymal cells fold over onto themselves to form a double-layered structure between the dura and pia, referred to as the arachnoid membrane. The passage of substances from the blood to the arachnoid membrane is prevented by the tight junctions between adjacent cells. The arachnoid membrane is generally, but not entirely, impermeable to hydrophilic substances and has a largely passive role in forming the blood-CSF barrier (23).

CP: First-Line Defense for the Brain

Lying within the central ventricular system, the CP is in an ideally suited position to monitor and modulate the functional status of the brain. The CP protects the brain against acute neurotoxic insults by using a complex, mul-tilayered detoxification system. First, the CP contains high concentrations of glutathione (GSH), cysteine, and metallothioneins that potently sequester toxic agents. Second, the CP uses protective enzymes, e.g., superoxide dismutase, GSH-S-transferase, and GSH peroxidase and reductase, to provide a barrier against free-radical oxidative stress. Third, the CP aids in the overall biodistribution of drugs and toxic compounds by using a full compliment of metabolizing enzymes, including phase I enzymes used for the functionalization of such drugs as cytochrome P-450 (CYP) isoform CYP2B1,2 and monoamine oxidase, phase II enzymes used for the conjugation of drugs (e.g., UDP-glucuronosyl transferase), and phase III activity, which provides "kidney-like" transport systems. These include indirectly coupled Na+/dicarboxylate cotransport and dicarboxylate/organic anion exchange, such as the organic anion transporter (OAT), the organic anion transporter polypeptide 1 (Oatpl) and Oatp2, and the multidrug resistance protein Mrpl/MRPl and ^-glycoprotein Mdrl/MDRl. Taken together, the CP contains the machinery needed to impede the entrance of noxious compounds to the brain and to control the efflux, binding, and metabolism of toxins.

CP and the Neuroimmune System

The CP also functions within the neuroimmune system. Traditionally, the CNS has been considered an immunologically privileged site, with no inherent need for immunosurveillance. The first indication that the CP-mediated interactions, as well as signaling between the peripheral immune system and the brain, came from evidence showing that the CP contains inducible lymphoid cells. The rapid and transient induction of interleukin (IL)-lP and tumor necrosis factor (TNF)-a following systemic lipopolysaccharide or IL-6 is a clear example of this interaction. This activation in the CP, and also in circumventricular organs, leptomeninges, and surrounding blood vessels, is the initiation of a process that ultimately spreads throughout the brain. This sequence suggests that CP transfers information between the peripheral immune system and the brain through a coordinated local induction of proinflammatory cytokines. Choroidal epithelial cells also constitutively express major histocompatibility complex (MHC) class II molecules, and class I molecules can be induced with such infectious agents as the rabies virus. In vitro, epithelial cells present foreign antigens and stimulate T-lymphocyte proliferation through a MHC class II-restricted mechanism. Accessory molecules that are important for leukocyte adhesion, such as L-selectin, intracellular cell adhesion molecule-1, and vascular cell adhesion molecule-1, are found at low levels on CP epithelial cells but can be upregulated during inflammatory conditions, experimental autoimmune encephalomyelitis. Other cells, including the Kolmer cells of the CP that normally act as phagocytic scavenger cells, also display induc-ible MHC class I and II antigens and proliferate when challenged with endotoxins. This antigen presentation capacity implies that the CP is part of an intrinsic surveillance system that defends against blood-borne pathogens and CSF-localized antigens.

The pathogen-induced inflammation within the CP is not surprising given the tropism that bacteria, parasites, and viruses (e.g., Neisseria meningitidis, Trypanosoma brucei, Sendai virus, lymphocytic choriomeningitis virus, mumps virus, and perhaps even human immunodeficiency virus (HIV)-1 and human T-cell leukemia virus 1 [HTLV-1]), have for the CP. HIV-infected T lymphocytes and monocytes are often observed in the stroma and supraepithelial portions of the CP, suggesting that the CP may be a pathway of entry for infected cells into the brain. HIV-1-positive cells are initially found in the subarachnoid and perivascular spaces but extend into the CSF of HIV-1- and HTLV-1-infected patients during the later stages of infection.

How infected leukocytes or activated T lymphocytes cross the CP is unknown, but it is intuitively obvious that their crossing can have disastrous consequences. The CP might be involved in the CNS entry of activated, myelin-directed autoreactive T lymphocytes during multiple sclerosis (MS). Activated T-lymphocyte infiltration into the brain results in the formation of demyelination plaques that underlie the clinical symptoms of MS. Because these plaques are frequently located in the periventricular area, the CP may constitute a preferential way for T lymphocytes to reach these structures. T lymphocytes and T-lymphocyte chemo-attractants are found in the CSF from MS patients.

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