Brain distribution control

Found in neurons of human brain by IHC found in glial cells of AD but not control brain CYP46 distribution differs in brains of control and AD patients (Bogdanovic et al, 2001). 

The selectivity of the SSRIs does not mean that they are totally without side effects. First, serotonin-secreting nerve cells are distributed throughout the brain and control a wide array of nervous system activities. As a result, increasing serotonin not only relieves depression, it can also produce many side effects such as abdominal discomfort, sexual dysfunction, and anxiety. Second, the selectivity of the SSRIs is not absolute but relative. Although the main action of the SSRIs is the same, they do have differences. For patients, this means that the drug interactions and side effects of the SSRIs vary somewhat. It also means that a patient who does not respond to one SSRI may respond to another. 

Yang S.C. et al.. Body distribution of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on the brain, J. Control. Rel., 59, 299, 1999. 

With cobra venom, the major effect is due to a toxin that acts on the nervous system. This neurotoxin is a small molecule, which can distribute throughout the body rapidly It acts like curare, paralysing the centre in the brain that controls breathing. By acting at the point where nerves control muscles it blocks the transmission of nerve impulses and causes muscle weakness and again affects breathing. The eyelids droop and speech becomes incoordinated. 

Parkinsonism is unique among diseases of the CNS, in that it results from the known loss of a particular NT, i.e. DA, resulting from the degeneration of a particular pathway, the nigrostriatal. Dopamine also has a relatively limited distribution in the brain and few peripheral effects. It should therefore be amenable to therapy based on augmenting its function. Also since the role of DA appears to be to maintain a tonic inhibitory control on GABA output pathways from the striatum, possibly in part by an extra synaptic action (Chapter 6), it may not be necessary for it to be released physiologically from nerve terminals. Thus it may be adequate to just provide DA extracellularly. 

The biosynthesis of adenosine is theoretically controlled by several processes namely (1) the biosynthesis of adenosine from AMP by 5 -nucleotidase [EC 3.1.3.5], (2) from S-adenosyl homocysteine by S-adenosyl homocystine hydrolase [EC 3.3.1.1], (3) the metabolism of adenosine to AMP by adenosine kinase [EC 2.7.1.20], and (4) to inosine by adenosine deaminase (ADA) [EC 3.5.4.2], Interestingly, both 5 -nucleotidase and ADA activities were found to be highest in the leptomeninges of rat brain in contrast, the adenosine kinase activity was widely distributed throughout the brain parenchyma, which has negligible ADA activity... 

Figure 5.1 Visualization of the distribution of the DA transporter, D3 receptor, and K2-opioid receptor in the human brain of a drug-free control subject and a representative cocaine overdose victim. (A, B) The DA transporter was measured using [3H]WIN 35,428 (2 nM) as described previously. (C, D) The D3 receptor was measured using [3H]-(+)-7-OH-DPAT (1 nM) in the presence of GTP (300 m/W) to enhance the selective labeling of the D3 receptor subtype over the D2 receptor subtype as described previously. (E, F) The K2-opioid receptor subtype was measured using [125l]IOXY on tissue sections pretreated with BIT and FIT to occlude binding to the p- and 8-opioid receptors, respectively.

Kusuhara, H. and Y. Sugiyama. Role of transporters in the tissue-selective distribution and elimination of drugs transporters in the liver, small intestine, brain and kidney. J. Control. Release 2002, 78, 43-54. 

Although tremendous progress has been made in characterizing the enzymes that control the synthesis and metabolism of cyclic nucleotides in the nervous system, our understanding of the regulation and interaction of these systems is far from complete. Work is now needed to definitively characterize, for each of these enzyme sub-types, its unique distribution pattern in the brain as well as its distinct functional and regulatory properties. 

---