Nervous system blood—nerve barrier

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. ... 

The nervous system is a vital part of the body. Certain protective mechanisms, primarily the blood-brain barrier (BBB) and, to a lesser extent, the blood-nerve barrier (BNB) shield the nervous system from the toxic chemicals in the blood. For example, the BBB is effective against many toxins, such as those of tetanus and diphtheria. Despite such protective barriers, certain chemicals may penetrate the brain and exhibit adverse effects to different degrees. This may be partly due to the absence of the BBB in certain sites, where the cells produce hormones or act as hormonal receptors. Substances that are highly lipophilic may readily cross the BBB and affect the brain. 

Another very important site for drug delivery is the central nervous system (CNS). The blood-brain barrier presents a formidable barrier to the effective delivery of most agents to the brain. Interesting work is now advancing in such areas as direct convective delivery of macromolecules (and presumably in the future macromolecular drug carriers) to the spinal cord [238] and even to peripheral nerves [239]. For the interested reader, the delivery of therapeutic molecules into the CNS has also been recently comprehensively reviewed... 

Poduslo JF, Curran GL, Gill JS. Pu-trescine-modified nerve growth factor bioactivity, plasma pharmacokinetics, blood-brain/nerve barrier permeability and nervous system biodistribution. 

As an alternative to targeting brain tumours which express the TfR, the transferrin approach can be used for the delivery of fusion proteins which bind to pharmacological receptors inside the central nervous system. An example of this is the construct consisting of nerve growth factor (NGF) and transferrin described in Section 11.8.2.3. The transferrin moiety in this type of construct will enable it to enter the brain, upon which the drug moiety will act by binding to its receptor. This approach seems especially suitable for compounds that cannot pass the blood-brain barrier, such as peptides and other hydrophilic substances. 

The most remarkable property of these derivatives of microbial natural products is the wide margin of safety accorded to treated mammals - the reason being that the drug does not readily cross the blood-brain barrier to any extent (18). Fortunately in mammals, GABA mediated nerves only occur in the central nervous system. 

Nerve cells are known to elaborate proteins that guide early development of the nervous system and in later life play a role in cell repair and regeneration. A purine that crosses the blood-brain barrier has shown activity similar to those endogenous factors in vitro as in in vivo models of nerve damage. Conjugate addition of adenine to ethyl acrylate in the presence of base leads to the ester (106). Reaction of that product with sodium... 

The toxins that inhibit the AChE are called anticholinesterase (anti-ChE) agents. They cause acetylcholine to accumulate in the vicinity of cholinergic nerve terminals, and thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems (Long, 1963). Nevertheless, several members of this class of compounds are widely used as therapeutics agents others that cross the blood-brain barrier have been approved or are in clinical trial for the treatment of Alzheimer s disease. 

The primary action is to bind irreversibly to the presyn-aptic nerve terminals of peripheral cholinergic nerve fibers. Because the drug does not penetrate the blood-brain barrier, it has no effect on the central nervous system. The binding of botulinum to the nerve terminals blocks the release of acetylcholine at the neuromuscular junction, resulting in a temporary paralysis of the muscle. 

Brain phospholipids. The brain is a rich source of phospholipids, and together with the spinal cord, it probably possesses the highest phospholipid content of any of the organs. There are many different types of phospholipids in the central nervous system. As they bypass the blood-brain barrier, adequate nutrition (biosynthesis) of the nerve cells is assured with these substances. Special... 

Scopolamine is a competitive bliKking agent of the parasympathetic nervous system as is atropine, but it differs markedly from atropine in its action on the higher nerve centers. Both drugs readily cross the blood-brain barrier and, even in therapeutic doses, cau.se confu.sion. particularly in the elderly. 

The binding of the nerve agent to the enzyme is considered irreversible unless removed by therapy. The accumulation of acetylcholine in the peripheral nervous system and central nervous system (CNS) leads to depression of the respiratory center in the brain, followed by peripheral neuromuscular blockade causing respiratory depression and death. The pharmacologic and toxicologic effects of the nerve agents are dependent on their stability, rates of absorption by the various routes of exposure, distribution, ability to cross the blood-brain barrier, rate of reaction and selectivity with the enzyme at specific foci, and their behavior at the active site on the enzyme. 

The nature of the nervous system is such that its integrity needs to be strongly preserved. The blood-brain barrier (BBB) restricts the entry of solute and is essential for the normal functioning of the CNS a similar barrier is a general feature of the nervous system of invertebrates as well as vertebrates and of peripheral nerves as well as the CNS. Although the BBB may be highly efficient at limiting access to... 

Catecholamine neurotransmitters in the central nervous system are synthesized in that location itself because they cannot cross the blood-brain barrier. However, dopa readily crosses the blood-brain barrier, promoting the catecholamine synthesis. Thus, in disorders involving deficiency of catecholamine synthesis, administration of dopa may have beneficial effects. In Parkinson s disease, in which deficiency of dopamine synthesis affects nerve transmission in the substantia nigra of the upper brain stem, administration of dopa leads to some symptomatic relief. Parkinsonism is a chronic, progressive disorder characterized by involuntary tremor, decreased motor power and control, postural instability, and muscular rigidity. 

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