And blood-brain barrier

Certain neutral technetium complexes can be used to image cerebral perfusion (Fig. 4). Those in Figure 4a and 4b have been approved for clinical use. Two other complexes (Fig. 4c and 4d) were tested in early clinical trials, but were not developed further. An effective cerebral perfusion agent must first cross the blood brain barrier and then be retained for the period necessary for image acquisition. Tc-bicisate is retained owing to a stereospecific hydrolysis in brain tissue of one of the ester groups to form the anionic complex TcO(ECD) , which does not cross the barrier. This mechanism of retention is termed metaboHc trapping. 

A number of quaternary amines are effective at modulating nerve transmissions. They often have the disadvantage of being relatively nonselective and so possess numerous sideeffects. This contrasts with the advantage that they do not cross the blood-brain barrier and so have no central sideeffects. Clo-... 

Temozolomide crosses the blood brain barrier and can be used for the treatment of brain tumors (e.g., glioblastoma multiforme). The most common side effects are nausea and vomiting. 

Local anaesthetics are more consistently effective than other therapies, but their use is controversial. High concentrations are needed for therapeutic benefit, but this also increases the amount crossing the blood brain barrier and entering the brain producing unwanted effects. Topical administration to the airways can reduce this. 

The area postrema is a circumventricular brain region positioned on the dorsal surface of the medulla on the floor of the fourth ventricle. The blood-brain barrier and the cerebrospinal fluid-brain barrier are absent in this region and consequently many substances that do not pass across capillaries in other regions of the brain can do so in the area postrema. The chemoreceptor trigger zone (CTZ), located in the lateral area postrema is sensitive to blood-borne emetogens. Nerves from the CTZ connect with the vomiting centre. 

NTS) in the medulla. The area postrema lacks a blood-brain barrier and is accessible to emetogens in the bloodstream. Neurons pass from the CTZ to the NTS and the vomiting centre. 

Extrahypothalamic OX-B-like immunoreactivity, reminiscent to that of CRF, has been described in clustered GABAergic neuronal populations, in the lateral division of central nucleus ofthe amygdala, the bednucleus of the stria terminalis, and in the hippocampus. Moreover, ectopic expression of preproorexin mRNA in the gut, ependymal cells, neuroblastomas, and of orexin receptors in adrenal gland, cancer and hematopietic stem cells suggests yet unexplored roles of orexins as paracrine factors controlling blood-brain barrier, and tumor or stem cell function. 

The symptoms of parkinsonism are caused by a depletion of dopamine in the CNS. Dopamine, when given orally, does not cross the blood-brain barrier and therefore is ineffective The body s blood-brain barrier is a mesh-work of tightly packed cells in die walls of the brain s capillaries that screen out certain substances. This unique meshwork of cells in the CNS prohibits large and potentially harmful molecules from crossing into die brain. This ability to screen out certain substances lias important implications for drug dierapy because some drugs are able to pass through die blood-brain barrier more easily dian odiers. 

Levodopa is a chemical formulation found in plants and animals that is converted into dopamine by nerve cells in the brain. Levodopa does cross die blood-brain barrier, and a small amount is dien converted to dopamine. This allows the drug to have a pharmacologic effect in patients witii Parkinson s disease (Pig. 29-1). Combining levodopa witii another drug (carbidopa) causes more levodopa to reach die brain. When more levodopa is available, the dosage of levodopa may be reduced. Carbidopa has no effect when given alone. Sinemet is a combination of carbidopa and levodopa and is available in several combinations (eg, Sinemet 10/100 has 10 mg of carbidopa and 100 mg of levodopa Sinemet CR is a time-released version of die combined drugs). 

D. J., Douglas C. L, Boules M., Stewart J.A., Zhao L., Lacy B., Cusack B., Fauq A., Richelson E. Peptide nucleic acids targeted to the neurotensin receptor and administered i.p. cross the blood-brain barrier and specifically reduce gene expression. Proc. Natl Acad. Sci. USA 1999 96 7053-7058. 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS (2009) IL-IR signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyehtis. J Immunol 183(l) 613-620 McEarland HE, Martin R (2007) Multiple sclerosis a complicated picture of autoimmunity. Nat Immunol 8 913-919... 

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

Once the malfunction of a particular NT has been established in a disease state, we need to find ways by which its activity can be restored to normal. The approaches used are indicated in Fig. 14.1 and outlined below. It is assumed that no NT crosses the blood-brain barrier and so its activity must be modified indirectly. 

ExCDDIs certainly improve the efficacy and duration of action of levodopa so that it can be given in a smaller dose (e.g. 25%) and generally in a 4 1 ratio, levodopa ExCDDI. As might be expected, some DA side-effects such as dyskinesia and psychoses are worse, but hypotension is less (no peripheral effects of DA) and vomiting is actually much reduced or abolished. This is because the chemoreceptor trigger zone of the vomiting centre while in the brain is on the blood side of the blood-brain barrier and will not be stimulated since no DA is formed peripherally (Fig. 15.5). That an... 

Since there is no reduction in striatal postsynaptic DA receptors in PD then drugs acting directly on them should be effective and in theory present some advantages over levodopa. They do not have to be converted to DA, they can be designed to be long-acting, cross the blood-brain barrier and act on specific DA receptors. In practice they have been somewhat disappointing. 

With most DA agonists there are the other expected signs of increased DA activity such as hallucinations, psychosis and hypotension which can be worse than with levodopa. Fortunately vomiting can be countered by giving the DA antagonist domperidone. This does not cross the blood-brain barrier and so counteracts only the peripheral (chemoreceptor trigger zone) effect of the DA agonist (Fig. 15.5). 

Tso and Lam suggested that astaxanthin could be useful for prevention and treatment of neuronal damage associated with age-related macular degeneration and may also be effective in treating ischemic reperfusion injury, Alzheimer s disease, Parkinson s disease, spinal cord injuries, and other types of central nervous system injuries. Astaxanthin was found to easily cross the blood-brain barrier and did not form crystals in the eye. 

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