27-Methylation pathway brain

The synthesis of phosphatidylcholine (Ptd-choline) in animal tissues is carried out chiefly by the cytidine nucleotide pathway, although base-exchange reaction and stepwise methylation of preexisting phosphatidylethanolamine (Ptd-ethanolamine) also contribute to its formation "7 The N-methylation pathway, first demonstrated in liver by Bremer and Greenberg and successively described in this tissue by several authors, has not been however unequivocally demonstrated in brain, and conflicting data have been produced in this c onnection, ... 

The problem of Ptd-ethanolamine methylation in brain was still open in 1977 viien experiments carried out in our laboratory at the same time on prostaglandin effect upon phospholipid metabolism in brain let us think that the methylation pathway was not only occurring in brain but was somewhat dependent upon the experimental conditions used. 

These findings, incidentally obtained during a study of different kind, indicated that methylation processes on lipid molecules in brain might be someidiat dependent upon experimental conditions and prompted a more complete study of the methylation pathway for lipid synthesis in brain. 

The data of the previous section have indicated that brain tissue is able to convert endogenous Ptd-ethanolamine to Ptd-choline by the stepwise methylation pathway. The fact that the addition of exogenous PDE brings about higher rate of Ptd-choline synthesis and the different results obtained at two different pH values with and without PDE addition already indicated that the methyl transferases acting upon membrane-bound Ptd-ethanolamine might be functioning at different pH optima. 

The physiological significance of this metabolic pathway in brain is unknown. Its occurrence in nervous tissue might be of some importance due to the possibility for the nerve cell to enrich its Ptd-choline fraction of polyunsaturated fatty acids, particularly 20 4 and 22 6, Moreover, the Ptd-choline synthesis by the methylation pathway in red blood cells has been indicated to represent a mechanism for an enzymeHnediated flip-flop of phospholipids from the cytoplasmic to the outer surface of erythrocyte m nbranes, producing fluidity variations in the same membrane vhich might affect ion movement and enzyme activities. It is possible that such implication can be drawn also for nervous membranes,... 

Pinally, the methylation pathway could represent an enzymic system linked to the source of choline in brain. It is known that the choline moiety as such cannot pass into the brain from the blood stream, but rather a lipid-choline moiety, probably lysophosphati-dylcholine, might be involved in the transport of the base. The methylation pathway, however, can be visualized as another means of producing choline in brain, provided Ptd-ethanolamine is transported into the brain. Conversely, due to the noticeable presence in the brain tissue of free serine, a possible pathway for choline production in brain may be represented by an exchange reaction between free serine and endogenous brain phospholipids, 9 20 cessive decarboxylation of phosphatidyl serine to Ptd-ethanolamine in the same tissue, finally followed by the described methylation reactions to produce a definite pool of active Ptd-choline,... 

The chromaffin cells of the adrenal medulla may be considered to be modified sympathetic neurons that are able to synthesize E from NE by /V-methylation. In this case the amine is Hberated into the circulation, where it exerts effects similar to those of NE in addition, E exhibits effects different from those of NE, such as relaxation of lung muscle (hence its use in asthma). Small amounts of E are also found in the central nervous system, particularly in the brain stem where it may be involved in blood pressure regulation. DA, the precursor of NE, has biological activity in peripheral tissues such as the kidney, and serves as a neurotransmitter in several important pathways in the brain (1,2). 

It could not be anticipated that the extension of the alpha-methyl of MDMA to an alpha-ethyl would also attenuate the effects of the compound on dopaminergic pathways in the brain. In contrast to MDMA, MBDB has no significant effect either on inhibition of uptake of dopamine into striatal synaptosomes (Steele et al. 1987) or on release of dopamine from caudate... 

Once returned to the presynaptic terminal, dopamine is repackaged into synaptic vesicles via the vesicular monoamine transporter (VMAT) or metabolized to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). Two alternative pathways are available for dopamine catabolism in the synapse, depending on whether the first step is catalyzed by MAO or catechol-O-methyltransferase (COMT). Thus, dopamine can be either deaminated to 3,4-dihydroxyphenylacetic acid (DOPAC) or methylated to 3-methoxytyramine (3-MT). In turn, deamination of 3-MT and methylation of DOPAC leads to homovanillic acid (HVA). In humans, cerebrospinal fluid levels of HVA have been used as a proxy for levels of dopaminergic activity within the brain (Stanley et al. 1985). 

The catecholamines dopamine, norepinephrine and epinephrine are neurotransmitters and/or hormones in the periphery and in the CNS. Norepinephrine is a neurotransmitter in the brain as well as in postganglionic, sympathetic neurons. Dopamine, the precursor of norepinephrine, has biological activity in the periphery, most particularly in the kidney, and serves as a neurotransmitter in several important pathways in the CNS. Epinephrine, formed by the N-methylation of norepinephrine, is a hormone released from the adrenal gland, and it stimulates catecholamine receptors in a variety of organs. Small amounts of epinephrine are also found in the CNS, particularly in the brainstem. 

The excitatoiy amino acids (EAA), glutamate and aspartate, are the principal excitatory neurotransmitters in the brain. They are released by neurons in several distinct anatomical pathways, such as corticofugal projections, but their distribution is practically ubiquitous in the central nervous system. There are both metabotropic and ionotropic EAA receptors. The metabotropic receptors bind glutamate and are labeled mGluRl to mGluRB. They are coupled via G-proteins to phosphoinositide hydrolysis, phospholipase D, and cAMP production. Ionotropic EAA receptors have been divided into three subtypes /V-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), and kainate receptors (Nakanishi 1992). 

Tolcapone [TOLE ka pone] is a nitrocatechol derivative that represents a new class of anti-Parkinson s drugs. It selectively and reversibly inhibits both peripheral and central catechol-O-methyl-transferase (COMT) (Figure 8.11). Normally, the methylation of levo-dopa by COMT to 3-O-methyldopa is a minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. Inhibition of COMT by tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Tolcapone has been demonstrated to reduce the frequency of the on-off phenomenon. 

A resonance unique to brain and nerve tissue and believed to be a specific marker for neurons (nerve cells) is V-acetylaspar-tate (NAA), structure 16-6, appearing at 2.0 ppm. NAA often decreases in the damaged brain tissue, suggesting that neurons have died. The damaged brain tissue also contains elevated lactate, structure 16-7, which is an indication that anaerobic metabolism, a pathway forced by oxygen deficit, is taking place. Only the methyl doublet of lactate (1.3 ppm) appears in the spectrum the methine quartet overlaps the water resonance and is normally never observed in vivo. 

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