Nervous system blood brain barrier protection

DOPA decarboxylase, a pyridoxal phosphate-requiring enzyme, catalyzes the synthesis of dopamine from DOPA. Dopamine is produced in neurons found in certain structures in the brain. It is believed to exert an inhibitory action within the central nervous system. Deficiency in dopamine production has been found to be associated with Parkinson s disease, a serious degenerative neurological disorder (Special Interest Box 14.3). The precursor l-DOPA is used to alleviate the symptoms of Parkinson s disease because dopamine cannot penetrate the blood-brain barrier. (The blood-brain barrier protects the brain from toxic substances. Many polar molecules and ions cannot move from blood capillaries, although most lipid-soluble substances readily pass across. The blood-brain barrier consists of connective tissue and specialized cells called astrocytes that envelop the capillaries.) Once l-DOPA is transported into appropriate nerve cells, it is converted to dopamine. 

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

In all higher species, locomotion is controlled by a central nervous system and, therefore, it might be argued that this system would provide an "ideal" target for toxins. However, when the nervous system is centrally located there is often in-built protection from blood-borne toxins and this "blood-brain" barrier offers protection, especially against large molecular weight toxins. 

Two additional features of the nervous system are particularly important to a discussion of neurotoxicity. The blood—brain barrier and the blood-nerve barrier act as protective devices for the nervous system, and are effective at preventing movement of certain chemicals from the blood to the brain and nerves. Unfortunately neither barrier is effective against all types of molecule, and there are plenty of examples of brain and nervous system toxicants that can penetrate the barriers. ... 

Although the CNS is protected from a number of xeno-biotics by the blood-brain barrier, the barrier is not effective against lipophilic compounds, such as solvents or insecticides (Fig. 7.1). Similarly, the peripheral nervous system is protected by a blood-neural barrier. The barriers are less well developed in the immature nervous system, rendering the fetus and neonate even more susceptible to neurotoxicants. Neural tissue susceptibility is due in large part to its high metabolic rate, high lipid content, and for the CNS, high rate of blood flow. 

The term blood-brain barrier (BBB) refers to the special obstacle that drugs encounter when trying to enter the brain from the circulatory system. The difference between the brain and other tissues and organs is that the capillaries in the brain do not have pores for the free flow of small molecules in the interstitial fluid of the brain. To enter the interstitial fluid, all molecules must cross a membrane. This design is a protective measure to defend the brain from unwanted and potentially hazardous xenobiotics. Traditionally, drugs that target the brain or central nervous system (CNS) cross the BBB by passive diffusion. Transport by carrier proteins across the BBB is becoming better understood but remains an area of active research. 

Central versus peripheral. The central nervous system comprises the brain and the spinal cord, which together are protected from the periphery by the blood brain barrier. 

Figure 7.6. Oiganisation of the autonomic nervous system, and the chemical types of synapses found within it. M Muscarinic, N Nicotinic cholinergic receptors D Dopaminergic, a, p Adrenergic receptors. (The irmervation of skeletal muscles by a-mo-toneurons is shown for comparison but not part of the autonomic system.) BBB Blood brain barrier. It protects the entire central nervous system, i.e. both the brain and the spinal cord.

The definition of neurotoxicity also indicates a potential difference between the developing and the mature nervous system, to underscore the fact that developmental neurotoxicity is an important aspect of neurotoxicology. Most known human neurotoxicants are indeed developmental neurotoxicants.4 In most, but not all cases, the developing nervous system is more sensitive to adverse effects than the adult nervous system, as indicated, for example, by the most deleterious effects of ethanol, methylmercury, or lead when exposure occurs in utero or during childhood. Furthermore, the blood-brain barrier (BBB), which protects the mature nervous system from the entry of a number of substances, appears to be poorly developed at birth and during the first few years of life.6... 

The concept of using carbamates as pretreatment which protects against OP intoxication was first mooted in 1956 by Koster who demonstrated that cats pretreated with a small dose of eserine (physostigmine) survived poisoning by supralethal doses of diisopropylphosphorofluori-date (DFP) (Koster, 1956). Subsequently, Berry and Davies (1970) demonstrated the effectiveness of a combination of atropine and carbamate pretreatment against soman poisoning. At that time, it was not considered that pretreatments with substances such as atropine, with marked actions on the central nervous system, would be acceptable for human use. For this reason, effort was concentrated upon pretreatment with pyridostigmine, a quaternary carbamate, which would not be expected to cross the blood-brain barrier and affect the central nervous system. 

The mechanism of fever induction has been studied most extensively. The brain is protected from the potentially harmful effects of biologically active substances or cells in the circulation by the blood-brain barrier, which is manifested by the extremely tight junctions between the endothelial cells lining blood capillaries,48 which prevent circulating substances of a particular size and chemical property (as well as cells) from entering the brain. Proinflammatory cytokines are of a sufficiently large size that makes it unlikely that they can pass the blood-brain barrier. However, numerous pathways to explain how cytokines produced in the periphery can influence central nervous system events have been studied. For example, highly localized... 

Once a compound has entered the systemic circulation it can be distributed aroimd the body in a matter of minutes. Whether or not it actually enters a particular tissue depends upon a variety of factors, but some tissues may be particularly susceptible whereas others may have extra protection. For instance, the central nervous system is surrounded by layers of lipid and protein collectively called the "blood-brain barrier" which protects it from water-soluble ionic compounds but it is readily pemeable to many fat-soluble substances. In different circumstances, depending upon the toxicity of the compounds involved, this may be either beneficial or damaging. 

During Amy Lloyd s evalnation, she developed a cardiac arrhythmia that was refractory to treatment. The extensive amyloid deposits in her heart had disrupted conduction of electrical impulses in the heart muscle, ultimately resulting in cardiac arrest. On autopsy, amyloid deposits were found within the heart, tongue, liver, adipose tissue, and every organ examined except the central nervous system, which had been protected by the blood-brain barrier. 

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