Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents

Kelley, Melissa H.; Kuroiwa, Masayuki; Taguchi, Noriko; Herson, Paco S.

doi:10.1016/j.neuropharm.2011.05.017

Cited by 28 publications

(23 citation statements)

References 31 publications

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“…Such modifications within the brain have implications on seizure susceptibility within the developing hippocampus and changing neuronal network environment. In addition, allopregnanolone and other neurosteroids could have differential neuroprotective effects in male and females experiencing potential excitotoxic or ischemic events that could damage neurons (Kelley et al, 2011). …”

Section: Sex-specific Differencesmentioning

confidence: 99%

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

2013

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Rationale Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal GABAa receptors are one of the prime molecular targets of neurosteroids. Objective This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAa receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAa receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAa receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAa receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. Conclusion The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAa receptors provide many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.

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Section: Sex-specific Differencesmentioning

confidence: 99%

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

2013

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“…ALLO at nanomolar concentrations binds to GABA A receptors and potentiates the action of endogenous GABA, whereas at micromolar concentrations ALLO directly activates GABA A receptors (Figure 1), and thus may be able to reduce neuronal death following TBI or other insults (Paul and Purdy, 1992; Lambert et al, 2001; Magnaghi et al, 2006). For example, P4 and ALLO protect cerebellar Purkinje cells in vitro and in vivo from ischemia (Ardeshiri et al, 2006; Kelley et al, 2008, 2011). Furthermore, P4 effects were mediated by ALLO acting through GABA A receptors: treatment with finasteride, a 5α-reductase inhibitor that prevents metabolism of P4 to ALLO, abolished the protective effects of P4 while administration of a GABA A receptor antagonist abolished neuroprotective effects of both P4 and ALLO (Ardeshiri et al, 2006).…”

Section: Effects Through γ-Amino Butyric Acid Type a (Gabaa) Receptorsmentioning

confidence: 99%

Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms

Cooke¹,

Nanjappa²,

Yang³

et al. 2013

Front. Neurosci.

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Traumatic brain injury (TBI) is an important and costly medical problem for which no clinically proven treatment currently exists. Studies in rodents and humans have shown beneficial effects of progesterone (P4) on both mortality and functional outcomes following TBI. Neuroprotective effects of P4 in TBI likely involve the classical nuclear progesterone receptors (Pgr) that are widely distributed in both glial cells and neurons of the brain. However, P4 may have critical effects not mediated through Pgr. In the brain, P4 is converted to a metabolite, allopregnanolone (ALLO), whose beneficial effects equal or exceed those of P4 in TBI. ALLO does not bind Pgr, suggesting it acts through non-classical pathways. ALLO has effects on GABAA and pregnane X receptors, as well as on the mitochondrial permeability transition pore. In addition, ALLO is metabolized to another compound, 5alpha-dihydroprogesterone, which binds Pgr, suggesting ALLO actions may involve signaling through Pgr as well as the aforementioned mechanisms of action. P4 and ALLO also signal through a number of membrane receptors (progesterone receptor membrane component 1, and membrane progesterone receptors (mPRs) alpha, beta, gamma, delta, and epsilon) in the brain that are distinct from Pgr, although the role of these receptors in the normal brain and in the therapeutic response to P4 and ALLO following TBI is unclear. In summary, P4 has the potential to become the first clinically effective treatment for TBI, and the effects of P4 and its metabolite ALLO in TBI may involve Pgr, mPRs, and other signaling pathways. Elucidating these mechanisms will more clearly reveal the potential of classical and non-classical pathways to mediate important effects of P4 and its metabolites, and potentially offer new therapeutic approaches to TBI.

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“…They receive and integrate excitatory inputs from sensory, vestibular and motor areas to allow for temporally and spatially precise movement (Thach, 1998; Bastian, 2006). There is evidence of Purkinje cell loss in post-mortem examinations of cardiac arrest victims and in rodent models of global cerebral ischemia however, the mechanism of injury to these cells remains understudied (Horn & Schlote, 1992; Welsh et al ., 2002; Lim et al ., 2004; Kelley et al ., 2011). …”

Section: Introductionmentioning

confidence: 99%

Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia

Quillinan¹,

Grewal²,

Deng³

et al. 2015

Neuroscience

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Motor deficits are present in cardiac arrest survivors and injury to cerebellar Purkinje cells (PCs) likely contribute to impairments in motor coordination and post-hypoxic myoclonus. NMDA receptor mediated excitotoxicity is a well-established mechanism of cell death in several brain regions, but the role of NMDA receptors in PC injury remains understudied. Emerging data in cortical and hippocampal neurons indicates that the GluN2A-containing NMDA receptors signal to improve cell survival and GluN2B-containing receptors contribute to neuronal injury. This study compared neuronal injury in the hippocampal CA1 region to that in PCs and investigated the role of NMDA receptors in PC injury in our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Analysis of cell density demonstrated a 24% loss of PCs within 24 hours after 8 min CA/CPR and injury stabilized to 33% by 7 days. The subunit promiscuous NMDA receptor antagonist MK-801 protected both CA1 neurons and PCs from ischemic injury following CA/CPR, demonstrating a role for NMDA receptor activation in injury to both brain regions. In contrast, the GluN2B antagonist, Co 101244, had no effect on Purkinje cell loss while protecting against injury in the CA1 region. These data indicate that ischemic injury to cerebellar PCs progresses via different cell death mechanisms compared to hippocampal CA1 neurons.

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Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents

Cited by 28 publications

References 31 publications

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms

Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia

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