Synthesis and Actions of 5a-R Metabolites of T in the Nervous System

[madman]

Abstract

Neuroactive testosterone metabolites synthesized by enzymes 5a-reductase and 3a/3b-hydroxysteroid oxidoreductase are critical physiological modulators of the central nervous system (CNS) function. Indeed, as discussed in this review, they exert a variety of effects on myelination, brain maturation, neurotransmission, reproductive behavior, and stress responses. The expression and synthesis of these enzymes as well as the levels of testosterone derivatives exhibit specific localized regional and sex differences in the CNS and are influenced under various physiological and neuropathological conditions. In addition, neuroactive metabolites of testosterone exert a variety of neuroprotective effects in several neuropathological animal models. Therefore, neuroactive testosterone metabolites might represent an interesting potential therapeutic option to treat some neurological disorders.




Introduction

Testosterone (T) and its various metabolites play an essential role in the physiology and pathophysiology of the central nervous system (CNS). For example, it is well established that androgens play a seminal role in brain development and neurogenesis and in sexual differentiation.1 Furthermore, androgens exerted a key role in CNS myelination and remyelination2 and provide neuroprotection effects on the hypothalamus in conditions of metabolic syndrome.3 Androgens are also thought to increase synaptic density in the gyrus dentatus4 and improve regional brain perfusion5 and enhance survival of new hippocampal neurons.6 T also mediates rewarding properties in the nucleus accumbens7 and its metabolite 3a-diol facilitates female sexual motivation when infused in the nucleus accumbens.8 T metabolites were thought to serve as an anxiolytic and cognitive-enhancing modulator in the hippocampus9 and T and its metabolites may modulate seizure susceptibility.10 T appears to regulate Alzheimer-like neuropathology in male 3xTg-AD mice11 and most recently it was demonstrated that blockade of 5a-reductase(5a-R) impedes cognitive performance, modifies dendritic morphology, and upregulates Tau phosphorylation in the hippocampus of male 3xTg-AD mice.12 In this review, we provide a discussion of the biology, biochemistry, and regional distribution of key enzymes involved in T metabolism in the nervous system, such as 5a-Rs and 3a/3b-hydroxysteroid oxidoreductases (3a/ 3b-HSORs) (Fig. 1), and discuss the critical role of such biochemical pathways and potential clinical implication on brain function in health and disease.




The Biology of 5a-R
-Expression and regional distribution of 5a-Rs in the CNS
-Biochemistry of 5a-Rs
-Molecular mechanisms of 5a-R catalysis and inhibition


*The Biology of 3a/3b-HSORs

*Physiological Effects of Testosterone Metabolites

*Levels of Testosterone Metabolites Under Physiological Conditions

*Levels of Testosterone Metabolites Under Pathological Conditions

*Neuroprotective Effects of Testosterone Metabolites




Conclusions

Significant literature indicating that 5a-Rs and 3a/3bHSORs are widely expressed and distributed in various regions of the nervous system suggests a critical function of these enzymes in the effects exerted by testosterone and its metabolites. Indeed, 5a-Rs catalyze a key rate-limiting step in the formation of 5a-reduced neuroactive steroids and, therefore, is critical in maintaining the physiological function of the nervous system. Indeed, T and its metabolites are implicated in processes of neurogenesis, myelination and remyelination, neuroprotection, and attenuation of neuroinflammation. Furthermore, these metabolites play an important role in the reduction of stress responses and modulation of behavior. Significant changes in the concentrations of testosterone and its various metabolites have been noted in the nervous system under various pathological conditions, such as neurodegenerative and psychiatric disorders. Altogether, observations reported in this review suggest that a better understanding of the biochemical actions of testosterone and its metabolites in the nervous system will have important clinical implications in the understanding of and the treatment of neurological disorders.

 

[madman]

FIG. 1. Androgen metabolism by the enzymes 5a-reductase and 3a/3b-hydroxysteroid oxidoreductase.

 

[madman]

FIG. 2. Mechanism of action of 5a-R. The action of the enzyme 5a-R on testosterone and other substrates is divided into three main steps: the first step (1) shows a nucleophilic attack of pyridine group from NADPH to testosterone leading to the binding to substrate with enzyme. The second step (2) consists of isomerization of the three keto group into the enole group and an abstraction of the pair of the electrons resulting in dissociation of NADP+ from the intermediate; the third step (3) shows the dissociation of 5aDHT from the enzyme-substrate complex and eventually the enzyme active site. 5a-DHT, 5adihydrotestosterone; 5a-R, 5a-reductase; NADPH, nicotine amide adenine dinucleotide phosphate.

 

[madman]

FIG. 3. Levels of testosterone metabolites in experimental models of neuropathological conditions. The arrows indicate the increase or decrease of testosterone metabolites, DHT, and 3a-diol. ALS, amyotrophic lateral sclerosis; CMT, Charcot-Marie-Tooth; CSF, cerebrospinal fluid; DHT, dihydrotestosterone; EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; PD, Parkinson’s disease; TBI, traumatic brain injury.

 

[madman]

FIG. 4. Neuroprotective effects of testosterone metabolites. The main protective effects of DHT and 3adiol are shown. 5a-DHT exerts a neuroprotective effect on (A) neuroinflammation in EAE, (B) damage of hippocampal neurons, (C) apoptosis induced by glutamate in cultured hippocampal neurons, (D) TBI, (E) spinal cord injury, (F) PD, (G) acute demyelination induced in cerebellar organotypic cultures. 5a-DHT or 3a-diol treatment improves (H) nerve conduction velocity and thermal sensitivity, in the experimental diabetic rat model, as well as reduces (I) neuropathic pain. Moreover, 3a-diol reduces ( J) morphological alterations in the sciatic nerve and (K) the accumulation of saturated fatty acids in the myelin of sciatic nerve of experimental diabetic rat model. This molecule is also able to exert beneficial effects on (L) painful symptoms in paclitaxel-induced peripheral neuropathy.

 

[Nelson Vergel]

This is such advanced information. I downloaded it and will try to make some sense of it.

It is strange that they did not review the upstream effects of 5 alpha reductase on neurosteroids like allopregnanolone.