Brain steroids

The most abundant natural steroid is cholesterol. It can be obtained in large quantides from wool fat (15%) or from brain or spinal chord tissues of fat stock (2-4%) by extraction with chlorinated hydrocarbons. Its saturated side-chain can be removed by chromium trioxide oxidation, but the yield of such reactions could never be raised above 8% (see page 118f.). 

Cholesterol is the central compound m any discussion of steroids Its name is a combination of the Greek words for bile (chole) and solid (stereos) preceding the characteristic alcohol suffix ol It is the most abundant steroid present m humans and the most important one as well because all other steroids arise from it An average adult has over 200 g of cholesterol it is found m almost all body tissues with relatively large amounts present m the brain and spinal cord and m gallstones Cholesterol is the chief constituent of the plaque that builds up on the walls of arteries m atherosclerosis... 

As we have seen in this chapter steroids have a number of functions in human physiology Cholesterol is a component part of cell mem branes and is found in large amounts in the brain Derivatives of cholic acid assist the digestion of fats in the small intestine Cortisone and its derivatives are involved in maintaining the electrolyte balance in body fluids The sex hormones responsible for mascu line and feminine characteristics as well as numerous aspects of pregnancy from conception to birth are steroids... 

Steroid Hormones and Neurosteroids. Steroids (qv) can affect neuroendocrine function, stress responses, and behavioral sexual dimorphism (78,79) (see Steroids). Mineralocorticoid, glucocorticoid, androgen, estrogen, and progesterone receptors are localized in the brain and spinal cord. In addition to genomic actions, the neurosteroid can act more acutely to modulate the actions of other receptors or ion channels (80). Pregnenolone [145-13-17, ( ) dehydroepiandosterone [53-43-0] C H2 02 (319) are excitatory neurosteroids found in rat brain, independent of adrenal... 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

It is known that the brain is one of the most sensitive sites of action of steroids in utero, and recently there have been suggestions that EDs may affect normal brain development and behaviour. For example, it has been alleged that in utero exposure to polychlorinated biphenyl compounds (PCBs) resulted in adverse effects on neurologic and intellectual function (memory and attention) in young children born to women who had eaten PCB contaminated fish in the USA." It has also been speculated that exposure to environmental pollutants with steroidal activity may be infinencing human sexual development and sexually controlled behavioiir." ... 

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

Neurosteroids are neuroactive steroids, which are synthesized in the brain. Neurosteroids can bind to and modulate the activity of y-aminobuty tie acidA(GABA A) receptors. 

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

McQueen, JK, Wilson, H, Sumner, BEH and Fink, G (1999) Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids. Molec. Brain Res. 63 241-247. 

Neurosteroids differ from nearly all the other transmitters and mediators in that they are lipid-soluble and can easily cross the blood-brain barrier. Thus it is necessary to distinguish those steroids that are produced in the brain from those that find their way there from the circulation after being released from the adrenal cortex or gonads. There are many natural and synthetic steroids that have some effect on neuronal function and can be considered neuroactive but few are actually produced in the brain to act on neurons, i.e. the true neurosteroids. 

Steroids which are found in the brain may be grouped as follows. The list is not... 

All these steroids disappear from the brain in animals after removal of the adrenals or gonads (ovary and testis). This also applies to tetrahydrodeoxycorticosterone for although it is formed by reduction of deoxycorticosterone within the brain, its synthesis depends on that steroid coming from the blood. 

These observations, while implicating steroids in brain function and behaviour, cannot be taken as a reliable indicator of their actual effect on neuronal function. Nevertheless, some neurosteroids produce CNS depression with a rapid inhibition of neuronal excitability and one progesterone derivative, alphaxalone (3a-hydroxy-5a pregnane-11, 20 dione, see Fig. 13.5) has been used effectively as an intravenous anaesthetic in humans. 

Intracellular steroid receptors, which alter gene expression, exist for corticosteroids, oestrogens and progesterone in the brain, as in the periphery but they cannot account for the relatively rapid depression of CNS function induced by some steroids. This was explained when Harrison and Simmonds (1984) discovered that alphaxalone (the steroid anaesthetic) potentiated the duration of GABA-induced currents at the GABAa receptor in slices of rat cuneate nucleus just like the barbiturates (Fig. 13.6). Of the... 

Harrison, NL and Simmonds, MA (1984) Modulation of the GABA receptor complex by a steroid anaesthetic. Brain Res. 323 287-292. 

Purdy, RH, Morrow, AL, Moore, PHJ and Paul, SM (1991) Stress-induced elevations of a amino butyric acid type A receptor-active steroids in the rat brain. Proc. Natl. Acad. Sci. USA 88 4553 557. 

Dantzer R. (1998). Vasopressin, gonadal steroids and social recognition. Prog Brain Res 119, 409-441. 

Lanthier A. and Patwardhan V.V. (1987). Effect of heterosexual olfactory and visual stimulation on 5a-en-3P hydroxysteroids and progesterone in the male rat brain. J Steroid Biochem 28, 697-701. 

Swann J. and Fiber J. (1997). Sex differences in function of a pheromonally stimulated pathway role of steroids and the main olfactory system. Brain Res Bull 44, 409-413. 

During phase I, each seizure causes a sharp increase in autonomic activity with increases in epinephrine, norepinephrine, and steroid plasma concentrations, resulting in hypertension, tachycardia, hyperglycemia, hyperthermia, sweating, and salivation. Cerebral blood flow is also increased to preserve the oxygen supply to the brain during this period of high metabolic demand. Increases in sympathetic and parasympathetic stimulation with muscle hypoxia can lead to ventricular arrhythmias, severe acidosis, and rhabdomyolysis. These, in turn, could lead to hypotension, shock, hyperkalemia, and acute tubular necrosis. 

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