Neuroprotective effects of allopregnenolone on hippocampal irreversible neurotoxicity in vitro

Frank, Claudio; Sagratella, S.

doi:10.1016/s0278-5846(00)00124-x

Cited by 56 publications

(36 citation statements)

References 9 publications

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“…Progesterone administration at the dose used in the present study results in a significant increase in the brain levels of DHP and THP (Ciriza et al, 2006). The reduced metabolites of progesterone mediate several of the effects of the hormone in the brain, including affective, cognitive, and neuroprotective actions (Frye, 1995;Frank and Sagratella, 2000;Frye and Scalise, 2000;Ciriza et al, 2004Ciriza et al, , 2006Djebaili et al, 2004Djebaili et al, , 2005He et al, 2004;. Our findings showing that the reduced derivatives of progesterone affect the phosphorylation of ERK-1/2 and Akt and the expression of PI3K in some brain regions suggest that progesterone metabolism may be involved in the hormonal effects on the MAPK and PI3K signaling pathways.…”

Section: Discussionmentioning

confidence: 70%

Regulation of the phosphoinositide‐3 kinase and mitogen‐activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain

Guerra‐Araiza

Amorim

Pinto‐Almazán

et al. 2008

J of Neuroscience Research

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Several growth factors, such as vascular endothelial growth factor, brain-derived neurotrophic factor, and insulin-like growth factor-I are involved in the actions of progesterone in the central nervous system. Previous studies in neuronal and glial cultures have shown that progesterone may regulate growth factor signaling, increasing the phosphorylation of extracellular-signal regulated kinase (ERK) and the phosphorylation of Akt, components of the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3 kinase (PI3K) signaling pathways, respectively. In this study, we have evaluated whether progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, regulate PI3K and MAPK signaling in the brain of ovariectomized rats in vivo. Significant increases in the phosphorylation of ERK, in the expression of the catalytic (p110) and the regulatory (p85) subunits of PI3K and in the phosphorylation of Akt were observed in the hypothalamus, the hippocampus, and the cerebellum 24 hr after progesterone administration. Progesterone metabolites partially mimicked the effect of progesterone and had a stronger effect on MAPK and PI3K signaling in the hypothalamus than in the other brain regions. These findings suggest that progesterone regulates MAPK and PI3K signaling pathways in the central nervous system in vivo by direct hormonal actions and by mechanisms involving progesterone metabolites.

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Section: Discussionmentioning

confidence: 70%

Regulation of the phosphoinositide‐3 kinase and mitogen‐activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain

Guerra‐Araiza

Amorim

Pinto‐Almazán

et al. 2008

J of Neuroscience Research

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“…Neurosteroids, including AP, also have neuroprotective functions (8), particularly in the hippocampal region. AP administration exerts a potent neuroprotective effects in cell viability studies in rat hippocampus slices and in primary hippocampal cultures as the steroid attenuates glutamate-induced increases of intracellular calcium (46). Thus, high levels of AP may protect the fetal brain; for example, neurosteroids that protect neurons after hypoxic or asphyxic episodes could be beneficial to the developing fetus.…”

Section: Discussionmentioning

confidence: 99%

Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in the Perinatal Sheep

et al. 2003

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Pregnane steroids have sedative and neuroprotective effects on the brain as a result of interactions with the steroid-binding site of the GABA A receptor. To determine whether the fetal brain is able to synthesize pregnane steroids de novo from cholesterol, we measured the expression of cytochrome P450 side-chain cleavage (P450scc) and 5␣-reductase type II (5␣RII) enzymes in fetal sheep from 72 to 144 d gestation (term~147 d) and in newborn lambs at 3 and 19-26 d of age. Both P450scc and 5␣RII expression was detectable by 90 d gestation in the major regions of the brain and also in the adrenal glands. Expression increased with advancing gestation and was either maintained at fetal levels or increased further after birth. In contrast, the relatively high content (200-400 pmol/g) of allopregnanolone (5␣-pregnan-3␣-ol-20-one), a major sedative 5␣-pregnane steroid, present throughout the brain from 90 d gestation to term, was reduced significantly (Ͻ50 pmol/g) immediately after birth. These results suggest that although the perinatal brain has the enzymes potentially to synthesize pregnane steroids de novo from cholesterol, either the placenta is a major source of these steroids to the brain or other factors associated with intrauterine life may be responsible for high levels of allopregnanolone production in the fetal brain until birth. Abbreviations AP, allopregnanolone, 5␣-pregnan-3␣-ol-20-one P450scc, P450 side chain cleavage enzyme 5␣RII, 5␣-reductase type II enzyme PMC, primary motor cortex GABA A ,␥-aminobutyric acid/benzodiazepine receptor 5␣-DHP, 5␣-dihydroprogesterone Neuroactive steroids such as allopregnanolone (AP) are potent neuromodulators that modify the excitability of the CNS by interaction with the ␥-aminobutyric acid/benzodiazepine receptor-chloride ionophore (GABA A receptor). In the adult AP is a positive allosteric modulator of the GABA A receptor with potent anxiolytic (1, 2), anticonvulsant (3, 4), sedative/ hypnotic, and anesthetic effects (5) on behavior. Prenatally, neuroactive steroids have been shown to suppress fetal activity in late gestation and seem to have a role in maintaining the low level of arousal-like behavior that typifies fetal life (6, 7). This interaction between AP and the GABA A receptor complex is responsible for the major pharmacologic actions of AP and is distinct from the genomic effects exerted by other steroids such as progesterone (8). In the brain, neuroactive steroids such as AP are synthesized de novo from cholesterol, but a proportion of the pool of steroids may be derived from precursors in blood that enter the brain across the blood-brain barrier (9 -11). Thus, peripheral steroidogenesis may influence neuroactive steroid content in the brain.The cytochrome P450 side-chain cleavage enzyme (P450scc) catalyzes the irreversible conversion of cholesterol to pregnenolone on the inner side of the mitochondrial membrane (12). The primary site of pregnenolone synthesis in the brain seems to be in oligodendrocytes and astrocytes, with significantly less synthesis occ...

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“…AP exerts a potent neuroprotective effect in cell viability studies with rat hippocampal slices and in primary hippocampal cultures as a result of the attenuation of glutamate-induced increases of intracellular calcium (40). GABA A receptor density has been shown to increase in the fetal brain between 85 and 128 d gestation such that adult concentrations are attained by 128 d. These receptors are highly sensitive to AP, with concentrations of 50 -150 nmol/L causing marked stimulation (41).…”

Section: Neurosteroids In the Compromised Fetusmentioning

confidence: 99%

Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in Fetal Sheep with Umbilicoplacental Embolization

et al. 2003

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Pregnane steroids have sedative and neuroprotective effects on the brain, due to interactions with the steroid-binding site of the GABA A receptor. In the adult brain, synthesis of the pregnane steroids is increased in response to stress. Therefore, we have used umbilicoplacental embolization to mimic chronic placental insufficiency during late gestation in sheep, to investigate the expression of the steroidogenic enzymes P450scc, 5␣-reductase type I (5␣RI), 5␣-reductase type II (5␣RII), and allopregnanolone (AP) content in the fetal brain. Umbilicoplacental embolization was induced from 114 d gestation (term~147 d) by daily injection of inert microspheres into the umbilical artery and continued for 17-23 d. Fetal arterial oxygen saturation was reduced to~60% of the preembolization value in each fetus, with a significant reduction in blood arterial PO 2 , pH, and plasma glucose concentrations (p Ͻ 0.05) and a significant increase in blood arterial PCO 2 and plasma lactate concentrations (p Ͻ 0.05). At postmortem at 131-137 d gestation, embolized fetuses were growth-restricted (2.10 Ϯ 0.14 kg, n ϭ 5) compared with agematched controls (4.43 Ϯ 0.56 kg, n ϭ 7, p Ͻ 0.05). Umbilicoplacental embolized fetuses showed increased P450scc expression in the primary motor cortex; 5␣RI expression was not changed in any of the regions examined, whereas 5␣RII expression was markedly increased in all brain regions. Brain AP content did not significantly change, whereas plasma concentrations were increased. These findings suggest that the increased expression of P450scc and 5␣RII may be a response that maintains AP concentration in the fetal brain after compromised placental function and/or intrauterine stress. Chronic hypoxemia and placental insufficiency are associated with fetal growth retardation (1). Generally, the brains of these growth-retarded fetuses are either not smaller, or are reduced to a lesser degree compared with the overall size of the fetus, suggesting that the brain is able to adapt to the intrauterine conditions that compromise fetal growth. On the other hand, growth-retarded and premature infants are at a greater risk of perinatal brain damage (2), indicating that some of these adaptive changes leave the brain more vulnerable to cytotoxic damage arising from a range of insults, such as acute hypoxia, asphyxia, or infection-induced inflammation.Pregnane steroids, including AP, modify the excitability of the CNS by interaction with the GABA A receptor at the steroid binding site. In the adult, AP has been shown to have potent anxiolytic (3, 4), anticonvulsant (5, 6), sedative/hypnotic, and anesthetic effects (7) on behavior. A constitutive role for neuroactive steroids in the developing brain was proposed after the observation that progesterone metabolites such as AP appear to maintain the low level of arousal-like behavior that typifies fetal life (8,9). In the rat, stressful stimuli of handling or swim stress have been shown to increase plasma AP content (10, 11), suggesting that modulation of the GABA A rece...

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Neuroprotective effects of allopregnenolone on hippocampal irreversible neurotoxicity in vitro

Cited by 56 publications

References 9 publications

Regulation of the phosphoinositide‐3 kinase and mitogen‐activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain

Regulation of the phosphoinositide‐3 kinase and mitogen‐activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain

Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in the Perinatal Sheep

Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in Fetal Sheep with Umbilicoplacental Embolization

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