CVOs are characterized by the small size, high permeability, and fenestrated capillaries. These barrier-deficient areas are recognized as important sites for communicating with the cerebrospinal fluid and between the brain and peripheral organs via blood-borne products. CVOs include the following structures65,66: Pineal gland, which is known as the regulatory organ of the circadian rhythm because

it produces the hormone melatonin from the amino acid tryptophan. Median eminence of the hypothalamus, which arises behind the optic chiasma and is continuous with the pituitary stalk; it communicates Inhibitors,research,lifescience,medical with the cerebrospinal fluid. Subfornical organ, which is positioned under the fornix and is one of the “sensory CVOs” responsible for maintaining body fluid balance. Area figure 2 postrema (AP), which is a CVO close to the nucleus of the solitary Inhibitors,research,lifescience,medical tract, part of the brain-stem bordering the fourth ventricle. The AP is another “sensory CVO” involved in body fluid homeostasis. It is also thought to play a role in emesis and vomiting. Subcommissural organ, which contacts the third ventricle covering the posterior commissure. It comprises Inhibitors,research,lifescience,medical a complex of neurosecretory ependymal cells known to secrete various glycoproteins into the cerebrospinal fluid. The functional significance of these glycoproteins has not yet been determined. Organum vasculosum of the lamina terminalis (OVLT), Inhibitors,research,lifescience,medical which is a

CVO close to the hypothalamic thermoregulatory center. The intermediate and neural lobes of the pituitary are right sometimes also cited as CVOs. Lesions of the OVLT suppressed intraperitoneal (IP) lipopolysaccharide (LPS)-induced fever67,68 and removal of AP-blocked IL-1-induced c-fos expression in the paraventricular nucleus,69 Inhibitors,research,lifescience,medical indicating the important role of these CVOs in transmitting the peripheral cytokines into the brain. However,

there are also controversial results, showing the opposite effect.70,71 The discrepant results may be attributable to the extent of the lesion and the different doses of LPS and IL-1 used in these studies. Altogether, it seems that low doses LPS and IL-1 may specifically affect the CVOs and high Cilengitide doses of LPS and IL-1 may gain access to CNS at other sites.72 Transmission via the vagus nerve The third pathway for cytokines to engage the CNS is the vagus nerve. Numerous studies have been published demonstrating the involvement of vagus nerve in peripheral cytokine-induced CNS responses. One of the first observations was that peripheral LPS-induced hyperalgesia can be blocked by vagotomy, indicating that afferent vagal pathways innervate specific regions of the brain as a key connection between peripheral cytokines and the CNS.73 Others reported the role of the vagus nerve in inducing fever,74 activating the HPA axis, depleting norepinephrine in the hypothalamus,75 prolonging slow- wave sleep,76 and suppressing food-motivated behavior.