Blood-brain barrier deficiency

Uhr M, Grauer MT (2003) abcblab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res 37 179-185 Uhr M, Sleekier T, Yassouridis A, Holsboer F (2000) Penetration of amitriptyhne, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption. Nemopsychopharmacology 22 380-387... 

Uhr, M., et al. 2000. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption. Neuropsychopharmacology 22 380. 

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. 

Dudley, A., Beliveau, R. P-glycoprotein deficient mouse in situ blood-brain barrier permeability and its predicfion using an in comho PAM PA model, (under review)... 

C. A. A. M., van der Valk, M. A., RobanusMandaag, E. C., Borst, P., Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood brain barrier and to increased sensitivity to drugs, Cell 1994, 77, 491-502. 

Other causes of PKU secondary to defective tetrahydrobiopterin synthesis include GTP cyclohydrolase deficiency and 6-pyravoyltetrahydrobiopterin synthase deficiency. Patients with either defect have psychomotor retardation, truncal hypotonia with limb hypertonia, seizures and a tendency to hyperthermia. The intravenous administration of BH4 may lower blood phenylalanine levels but this cofactor may not readily cross the blood-brain barrier. Treatment with synthetic pterin analogs or supplementation with tryptophan and carbidopa may prove more efficacious, particularly if treatment is started early in life. 

Defective transport of glucose across the blood-brain barrier is caused by deficiency in the glucose transporter protein 703... 

Starvation may be associated with an increase in the permeabflity of the blood-brain barrier (Hawkins 1986, as cited in Dybing and Spderlund 1999). Tissue antioxidant status may be compromised under nutritional deficiencies and starvation (Godin and Wohaieb 1988, as cited in Dybing and Spderlund 1999). 

Medicinal chemistry has many examples of the development of successful therapeutics based on an exploration of endogenous compounds. The treatment of diabetes mellitus, for example, is based upon the administration of insulin, the hormone that is functionally deficient in this disease. The current treatment of Parkinson s disease is based upon the observation that the symptoms of Parkinson s disease arise from a deficiency of dopamine, an endogenous molecule within the human brain. Since dopamine cannot be given as a drug since it fails to cross the blood-brain barrier and enter the brain, its biosynthetic precursor, L-DOPA, has been successfully developed as an anti-Parkinson s drug. Analogously, the symptoms of Alzheimer s disease arise from a relative deficiency of acetylcholine within the brain. Current therapies for Alzheimer s-type dementia are based upon the administration of cholinesterase... 

Since Parkinson s disease arises from a deficiency of DA in the brain, the logical treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be done with DA because it does not cross the blood-brain barrier. However, high doses (3-8 g/day, orally) of L(-)-DOPA (levodopa), a prodrug of DA, have a remarkable effect on the akinesia and rigidity. The side effects of such enormous doses are numerous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the administration of smaller doses, and also prevents the metabolic formation of peripheral DA, which can act as an emetic at the vomiting center in the brainstem where the blood-brain barrier is not very effective and can be penetrated by peripheral DA. 

Nitta, T., et al. 2003. Size-selective loosening of the blood-brain barrier in claudin-5 deficient mice. 

Drug Levodopa Mechanism of Action Resolves dopamine deficiency by being converted to dopamine after crossing blood-brain barrier. Special Comments Still the best drug for resolving parkinsonian symptoms long-term use limited by side effects and decreased efficacy. 

Because the underlying problem in Parkinson disease is a deficiency of dopamine in the basal ganglia, simple substitution of this chemical would seem to be a logical course of action. However, dopamine does not cross the blood-brain barrier. Administration of dopamine either orally or parenterally will therefore be ineffective because it will be unable to cross from the systemic circulation into the brain where it is needed. Fortunately, the immediate precursor to dopamine, dihydroxyphenylalanine (dopa Fig. 10-2), crosses the blood-brain barrier quite readily. Dopa, or more specifically levodopa (the L-isomer of dopa), is able to cross the brain capillary endothelium through... 

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