Abstract:Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). The discovery that such steroids are locally synthesised in the central nervous system (CNS) promoted the thesis that neural inhibition in the CNS may be “fine‐tuned” by these neurosteroids to influence behaviour. In preclinical studies, these neurosteroids exhibited anxiolytic, anticonvulsant, analgesic and sedative proper… Show more
“…In the brain, AlloP exerts rapid actions to downregulate CRF gene expression in the hypothalamus [ 64 ], reduce circulating glucocorticoid production [ 65 , 66 ], and to restore homeostasis as an endogenous modulator of the HPA axis. The protective effects of AlloP over gp120 have not been established but should be investigated given that AlloP is an FDA-approved therapy [ 67 ].…”
Despite the benefits of combinatorial antiretroviral therapies (cART), virotoxic HIV proteins are still detectable within the central nervous system. Approximately half of all cART-treated patients contend with neurological impairments. The mechanisms underlying these effects likely involve virotoxic HIV proteins, including glycoprotein 120 (gp120). Glycoprotein-120 is neurotoxic due to its capacity to activate microglia. Corticosterone has been found to attenuate neuronal death caused by gp120-induced microglial cytokine production in vitro. However, the concentration-dependent effects of corticosterone on microglial activation states and the associated behavioral outcomes are unclear. Herein, we conducted parallel in vitro and in vivo studies to assess gp120-mediated effects on microglial activation, motor function, anxiety- and depression-like behavior, and corticosterone’s capacity to attenuate these effects. We found that gp120 activated microglia in vitro, and corticosterone attenuated this effect at an optimal concentration of 100 nM. Transgenic mice expressing gp120 demonstrated greater anxiety-like behavior on an elevated plus maze, and a greater duration of gp120 exposure was associated with motor deficits and anxiety-like behavior. Circulating corticosterone was lower in gp120-expressing males and diestrous females. Greater circulating corticosterone was associated with reduced anxiety-like behavior. These findings may demonstrate a capacity for glucocorticoids to attenuate gp120-mediated neuroinflammation and anxiety-like behavior.
“…In the brain, AlloP exerts rapid actions to downregulate CRF gene expression in the hypothalamus [ 64 ], reduce circulating glucocorticoid production [ 65 , 66 ], and to restore homeostasis as an endogenous modulator of the HPA axis. The protective effects of AlloP over gp120 have not been established but should be investigated given that AlloP is an FDA-approved therapy [ 67 ].…”
Despite the benefits of combinatorial antiretroviral therapies (cART), virotoxic HIV proteins are still detectable within the central nervous system. Approximately half of all cART-treated patients contend with neurological impairments. The mechanisms underlying these effects likely involve virotoxic HIV proteins, including glycoprotein 120 (gp120). Glycoprotein-120 is neurotoxic due to its capacity to activate microglia. Corticosterone has been found to attenuate neuronal death caused by gp120-induced microglial cytokine production in vitro. However, the concentration-dependent effects of corticosterone on microglial activation states and the associated behavioral outcomes are unclear. Herein, we conducted parallel in vitro and in vivo studies to assess gp120-mediated effects on microglial activation, motor function, anxiety- and depression-like behavior, and corticosterone’s capacity to attenuate these effects. We found that gp120 activated microglia in vitro, and corticosterone attenuated this effect at an optimal concentration of 100 nM. Transgenic mice expressing gp120 demonstrated greater anxiety-like behavior on an elevated plus maze, and a greater duration of gp120 exposure was associated with motor deficits and anxiety-like behavior. Circulating corticosterone was lower in gp120-expressing males and diestrous females. Greater circulating corticosterone was associated with reduced anxiety-like behavior. These findings may demonstrate a capacity for glucocorticoids to attenuate gp120-mediated neuroinflammation and anxiety-like behavior.
“…Probably the most studied mechanism of action of neuroactive steroids is the interaction with the GABA A receptor, 6 which has the possibility of influencing a wide number of circuits, functions and behavior. In humans, 7,8 elevated allopregnanolone levels are associated with disorders such as catamenial epilepsy, premenstrual disorder, hepatic encephalopathy, polycystic ovarian syndrome, increased negative mood, disturbed memory and increased food intake in some individuals.…”
Section: Figurementioning
confidence: 99%
“…In humans, 7,8 elevated allopregnanolone levels are associated with disorders such as catamenial epilepsy, premenstrual disorder, hepatic encephalopathy, polycystic ovarian syndrome, increased negative mood, disturbed memory and increased food intake in some individuals. The review by Belelli et al 6 provides a history of the discovery and properties of interactions among neuroactive steroids and GABA A receptor, highlighting the difficulties found in clinical applications. However, in this context, it is important to note that the recent approval by the Food and Drug Administration in the USA for the use of allopregnanolone (brexanolone) when treating postpartum depression has again stimulated enthusiasm for exploring the potential of neuroactive steroids as new therapeutic strategies for treating psychiatric disorders.…”
“…We chose to employ a neurosteroid-based agent. Neurosteroids and analogues can have a wide range of GABAergic action and many are known to generate sedation and anesthesia (e.g., refs − ). Neurosteroids and analogues have several advantages over other classes of GABAergic agents.…”
Activation of the GABA A receptor is associated with numerous behavioral end points ranging from anxiolysis to deep anesthesia. The specific behavioral effect of a GABAergic compound is considered to correlate with the degree of its functional effect on the receptor. Here, we tested the hypothesis that a low-efficacy allosteric potentiator of the GABA A receptor may act, due to a ceiling effect, as a sedative with reduced and limited action. We synthesized a derivative, named (3α,5β)-20methyl-pregnane-3,20-diol (KK-235), of the GABAergic neurosteroid 5β-pregnane-3α,20α-diol. Using electrophysiology, we showed that KK-235 is a low-efficacy potentiator of the synaptictype α1β2γ2L GABA A receptor. In the zebrafish larvae behavioral assay, KK-235 was found to only partially block the inverted photomotor response (PMR) and to weakly reduce swimming behavior, whereas the high-efficacy GABAergic steroid (3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile (ACN) fully blocked PMR and spontaneous swimming. Coapplication of KK-235 reduced the potentiating effect of ACN in an electrophysiological assay and dampened its sedative effect in behavioral experiments. We propose that low-efficacy GABAergic potentiators may be useful as sedatives with limited action.
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