Blood-brain carrier

Unfortunately, the preparation went wrong, and significant amounts ofMPTP, a neurotoxin, were produced. MPTP can cross the blood-brain carrier and it is then converted to MPP+, which causes the symptoms of Parkinson s disease. This resulted in the so-called case of the frozen addicts (J.W. Langston and J. Palferman, Vintage Books 1996). 

Kerper LE, Ballatori N, Clarkson TW. 1992. Methylmercury transport across the blood-brain barrier by an amino acid carrier. Am J Physiol 262 R761-R765. 

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... 

Drug-Carrier Transporters at the Blood-Brain Barrier... 

Transferrin is an iron carrier protein that acts as a trophic survival factor for neurons, astrocytes and OLs. As the blood-brain barrier becomes established during development, neural cells become dependent on transferrin produced by OLs and choroid plexus epithelial cells (Fig. 25-14). OLs are the major source of transferrin in the CNS. This suggests an important function for OLs in... 

P. Tornquist and A. Aim. Carrier-mediated transport of amino acids through the blood-retinal and the blood-brain barriers. Graefes Arch, Clin. Exp. Ophthalmol. 224 21-25 (1986). 

Isolated capillaries have been used for a long time to study transport and metabolic function of the blood-brain barrier [61, 72, 75, 76, 78, 87-91], In contrast to monolayer cell cultures, which are susceptible to induction or inhibition of carrier protein expression, experiments with freshly isolated capillaries directly reflect the situation at the luminal side of brain capillaries. 

The proposal that the effects of heroin are mediated chiefly by its deacetylated metabolites, morphine and 6-monoacetylmorphine (MAM) [28], and that heroin (and MAM) function primarily as carriers to facilitate morphine availability at C.N.S. receptor sites is supported by studies in new-born rats [29]. While rats show a pronounced increase in their resistance to morphine 16 days afterbirth (probably associated with development of a blood-brain barrier), there is little change in toxicity to heroin with increasing age hence ready access of heroin to the brain is concluded, even after the barrier has developed. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxy-phenylalanine (levodopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed, likely causing undesirable effects (tachycardia, arrhythmias resulting from activation of Pi-adrenoceptors [p. 114], hypotension, and vomiting). Extracerebral production of dopamine can be prevented by inhibitors of DOPA-decarboxylase (car-bidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. Excessive elevation of brain dopamine levels may lead to undesirable reactions, such as involuntary movements (dyskinesias) and mental disturbances. 

There is evidence in literature that alkaloid biology is connected with regulation, stimulation and induction functions. Tsai et al. proved that caffeine levels in the blood, brain and bile of rats decreased when given a treatment of rutaecarpine, an alkaloid from Evodia rutaecarpa (Figure 78). It is known that caffeine has been found to enter the brain by both simple diffusion and saturable carrier-mediated transport . The hepatobiliary excretion of caffeine has also been reported in humans rabbits and rats. ... 

The other major class of transporter protein is the carrier protein. A prototypic example of a carrier protein is the large neutral amino acid transporter. An important function of the LNAA transporter is to transport molecules across the blood-brain barrier. As discussed previously, most compounds cross the BBB by passive diffusion. However, the brain requires certain compounds that are incapable of freely diffusing across the BBB phenylalanine and glucose are two major examples of such compounds. The LNAA serves to carry phenylalanine across the BBB and into the central nervous system. Carrier proteins, such as the LNAA transporter, can be exploited in drug design. For example, highly polar molecules will not diffuse across the BBB. However, if the pharmacophore of this polar molecule is covalently bonded to another molecule which is a substrate for the LNAA, then it is possible that the pharmacophore will be delivered across the BBB by hitching a ride on the transported molecule. 

MPTP is also metabolized by other routes involving cytochromes P-450, FAD-dependent monooxygenases, and aldehyde oxidase. However, these seem to be detoxication pathways, as they divert MPTP away from uptake and metabolism in the brain. However, MPTP may inhibit its own metabolism by cytochromes P-450 and thereby reduce one means of detoxication. This example illustrates the importance of structure and physicochemical properties in toxicology. MPTP is sufficiently lipophilic to cross the blood-brain barrier and gain access to the astrocytes. The structure of the metabolite is important for uptake via the dopamine system, hence localizing the compound to a particular type of neuron. Again, uptake into mitochondria is presumably a function of structure, as a specific energy-dependent carrier is involved. 

MPTP is a molecule, which is sufficiently lipophilic to cross the blood-brain barrier and enter the astrocyte cells. Once in these cells, it can be metabolized by monoamine oxidase B to MPDP and then MPP both of which are charged molecules. These metabolites are therefore not able to diffuse out of the astrocyte into the bloodstream and away from the brain. However, the structure of MPP allows it to be taken up by a carrier system and concentrated in dopaminergic neurones. In the neurone, it inhibits the mitochondrial electron transport chain leading to damage to the neurone. 

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