PREGNENOLONE and other NEUROSTEROIDS: Relation to Amyloid Beta, the Hippocampus and the Pre Frontal Cortex. The present study shows for the first time that injection of Amyloid beta into the hippocampal CA1 sub-region of rats reduces levels of pregnenolone and progesterone, in the prefrontal cortex and hippocampus In this study Amyloid beta (Aβ25-35) injected into the bilateral hippocampus CA1 region significantly reduced learning and memory. At the biochemical level, hippocampal levels of pregnenolone were significantly reduced with Amyloid beta treatment. Furthermore, Aβ25–35 up-regulates the expression of pro-inflammatory cytokines, TNF-α and IL-1β. Progesterone reverses Aβ25–35-mediated impairment and thus, may be a potential therapeutic strategy for AD. Steroid hormones and their metabolites within the central nervous system are commonly defined as neuroactive steroids or neurosteroids[11]. They can be synthesized de novo from cholesterol by glial cells and neurons, or synthesized in the periphery by the adrenal glands and gonads[12]. Pregnenolone is the first hormone in the pathway that generates a host of key neurohormones in the brain that are known to affect nerve cell growth and to modulate various moods. The conversion of cholesterol to pregnenolone constitutes the first of many steps in the synthesis of some of the body’s key hormones, including dehydroepiandrosterone (DHEA), testosterone, progesterone, estrogen, and cortisol. We have a long standing interest in Pregnenolone as a readily available aid to memory and attention (and there have been studies showing as association between ADHD and reduced levels of Pregnenolone. Nicknamed “the mother hormone,” pregnenolone is a vital building block,being the very first (and arguably the most versatile) hormone in a cascade of molecular events. The concentration of neuroactive steroids is higher in the central nervous system than in the periphery. Neuroactive steroids mainly include pregnenolone and dehydroepiandrosterone (their sulfate derivatives, pregnenolone sulfate and dehydroepiandrosterone sulfate), and progesterone, 5α-dihydroprogesterone, 3α, 5α-tetrahydroprogesterone (allopregnanolone), deoxycorticosterone, tetrahydrodeoxycorticosterone, and estradiol. The levels of Progesterone produced in the brain are no doubt dependent on the availability of Pregenenolone to serve as a precursor. Neuroactive steroids play an important role as rapid endogenous modulators of neuronal excitability However, no specific receptor has been reported for neuroactive steroids thus far. Most of their actions in the nervous tissue were reported as a modulation of membrane neurotransmitter receptors, such as γ-amino butyric acid, N-methyl-D-aspartate, and sigma 1 receptors thus affecting neuronal plasticity, anxiety, responses to stressful stimuli, and neuropsychiatric symptoms represented during AD Although neuroactive steroids are known to be neuroprotective, changes in their level during AD and their role in Aβ-mediated cognitive impairment remain elusive given the limitation in sample sizes and analysis methods[ Previous findings have indicated that neuroactive steroids are associated with the pathological processes of several disorders, including diabetes mellitus, social isolation, and traumatic brain injury[. Recently, several studies have reported the alterations of levels of neuroactive steroids in AD patients A general trend of lower levels of neuroactive steroids was observed in different brain regions of AD patientsHowever, the relationship between Aβ and neuroactive steroids remains elusive. Previous studies on postmortem brain tissue of AD patients have suggested that reduced levels of neuroactive steroids may increase the risk of AD To gain a better understanding on the role of neuroactive steroids in the pathology of AD, the present study investigated the effect of progesterone administration against Aβ25–35-induced impairment in vivo. Findings from this analysis revealed that pregnenolone and progesterone were decreased in Amyloid beta-treated rats In line with these reports, this study showed that intracerebral injection of aggregated Aβ25–35 into the bilateral hippocampal CA1 region induced cognitive deficits. In the present study, Amyloid beta injected into the bilateral hippocampus CA1 region significantly reduced learning and memory. At the biochemical level, hippocampal levels of pregnenolone were significantly reduced with Aβ25–35 treatment. Furthermore, progesterone was considerably decreased in the prefrontal cortex and hippocampus, This is the first report showing that Aβ25–35, a main etiological factor of Alzheimers disease, can alter the level and metabolism of neuroactive steroids in the prefrontal cortex and hippocampus, which are brain regions significantly involved in learning and memory. Aβ25–35 exposure also increased the expression of inflammatory mediators, tumor necrosis factor-α and interleukin-1β. However, subcutaneous injection of progesterone reversed the upregulation of tumor necrosis factor-α and interleukin-1β in a dose-dependent manner. Concomitant with improved cognitive abilities, progesterone blocked Aβ-mediated inflammation and increased the survival rate of hippocampal pyramidal cells. The authors of the study hypothesize that Aβ-mediated cognitive deficits may occur via changes in neuroactive steroids. The findings provide a possible therapeutic strategy for Alzheimers disease via neuroactive steroids, particularly progesterone. ncbi.nlm.nih.gov/pmc/articles/PMC4146013/ FULLTEXT
Posted on: Mon, 20 Oct 2014 04:38:42 +0000
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