Castration alters susceptibility of male rats to specific seizures

Thomas, J. A.; McLean, Jack H.

doi:10.1016/0031-9384(91)90347-q

Cited by 30 publications

(13 citation statements)

References 7 publications

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“…The incidence of epilepsy is approximately 15% higher in men than in women, and men with epilepsy exhibit testosterone deficiency. Studies in animals have shown that decreased testosterone is associated with higher incidences of seizures and replacement with testosterone attenuates seizures (Thomas and McLean, 1991;Reddy, 2008). Because testosterone elevates seizure threshold via androstanediol (Reddy, 2004b), a decrease in testosterone levels, such as occur in hypogonadism and enzyme-inducing drug therapy (Herzog et al, 2006), may therefore contribute to seizure exacerbation.…”

Section: Discussionmentioning

confidence: 99%

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA_A Receptors

Reddy

Jian²

2010

J Pharmacol Exp Ther

149

127

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Testosterone modulates seizure susceptibility, but the underlying mechanisms are obscure. Recently, we demonstrated that testosterone affects seizure activity via its conversion to neurosteroids in the brain. Androstanediol (5␣-androstan-3␣,17␤-diol) is an endogenous neurosteroid synthesized from testosterone. However, the molecular mechanism underlying the seizure protection activity of androstanediol remains unclear. Here, we show that androstanediol has positive allosteric activity as a GABA A receptor modulator. In whole-cell recordings from acutely dissociated hippocampus CA1 pyramidal cells, androstanediol (but not its 3␤-epimer) produced a concentration-dependent enhancement of GABA-activated currents (EC 50 of 5 M). At 1 M, androstanediol produced a 50% potentiation of GABA responses. In the absence of GABA, androstanediol has moderate direct effects on GABA A receptor-mediated currents at high concentrations. Systemic doses of androstanediol (5-100 mg/kg), but not its 3␤-epimer, caused dose-dependent suppression of behavioral and electrographic seizures in mouse hippocampus kindling, which is a model of temporal lobe epilepsy. The ED 50 value for antiseizure effects of androstanediol was 50 mg/kg, which did not produce sedation/motor toxicity. At high (2ϫ ED 50 ) doses, androstanediol produced complete seizure protection that lasted for up to 3 h after injection. The estimated plasma concentrations of androstanediol producing 50% seizure protection in the kindling model (10.6 M) are within the range of concentrations that modulate GABA A receptors. These studies suggest that androstanediol could be a neurosteroid mediator of testosterone actions on neuronal excitability and seizure susceptibility via its activity as a GABA A receptor modulator and that androstanediol may play a key role in men with epilepsy, especially during the age-related decline in androgen levels.

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Section: Discussionmentioning

confidence: 99%

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA_A Receptors

Reddy

Jian²

2010

J Pharmacol Exp Ther

149

127

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“…On the contrary, testosterone and related androgens have protective effects against seizures induced by pentylenetetrazol and kainic acid (Schwartz-Giblin et al, 1989; Frye and Reed, 1998; Frye et al, 2001a,b; Reddy, 2004b). Moreover, studies in orchidectomized or castrated animals have shown that decreased testosterone is associated with higher incidence of seizures and replacement with testosterone attenuates seizures (Grigorian and Khudaverkian, 1970; Thomas and McLean, 1991; Pericić et al, 1996; Pesce et al, 2000). It is demonstrated that testosterone modulation of seizure susceptibility occurs through its conversion to neurosteroids with “anticonvulsant” and “proconvulsant” actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites within the brain (Reddy, 2004a,b).…”

Section: Role Of Steroid Hormones In Epileptogenesismentioning

confidence: 99%

Role of hormones and neurosteroids in epileptogenesis

Reddy

2013

Front. Cell. Neurosci.

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This article describes the emerging evidence of hormonal influence on epileptogenesis, which is a process whereby a brain becomes progressively epileptic due to an initial precipitating event of diverse origin such as brain injury, stroke, infection, or prolonged seizures. The molecular mechanisms underlying the development of epilepsy are poorly understood. Neuroinflammation and neurodegeneration appear to trigger epileptogenesis. There is an intense search for drugs that truly prevent the development of epilepsy in people at risk. Hormones play an important role in children and adults with epilepsy. Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect seizure activity in animal models and in clinical studies. However, the impact of hormones on epileptogenesis has not been investigated widely. There is emerging new evidence that progesterone, neurosteroids, and endogenous hormones may play a role in regulating the epileptogenesis. Corticosterone has excitatory effects and triggers epileptogenesis in animal models. Progesterone has disease-modifying activity in epileptogenic models. The antiepileptogenic effect of progesterone has been attributed to its conversion to neurosteroids, which binds to GABA-A receptors and enhances phasic and tonic inhibition in the brain. Neurosteroids are robust anticonvulsants. There is pilot evidence that neurosteroids may have antiepileptogenic properties. Future studies may generate new insight on the disease-modifying potential of hormonal agents and neurosteroids in epileptogenesis.

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“…The potential molecular pathways for the testosterone modulation of seizure activity are illustrated in Figure 3. Testosterone is known to produce both proconvulsant and anticonvulsant effects depending on the animal model and the seizure type (Werboff and Havlena, 1968;Thomas and McLean, 1991;Frye and Reed, 1998;Pesce et al, 2000;Mejias-Aponte et al, 2002). Both animal and clinical studies show that testosterone enhances seizure activity by metabolism to estrogens (Isojarvi et al, 1988;Thomas and Yang, 1991;Herzog et al, 1998;Edwards et al, 1999;El-Khayat et al, 2003).…”

Section: Effect Of Testosterone On Seizure Susceptibilitymentioning

confidence: 99%

“…On the contrary, testosterone and related androgens have protective effects against seizures induced by pentylenetetrazol and kainic acid (Schwartz-Giblin et al, 1989;Frye and Reed, 1998;Frye et al, 2001a;Reddy, 2004b). Moreover, studies in orchidectomized or castrated animals have shown that decreased testosterone is associated with higher incidence of seizures and replacement with testosterone attenuates seizures (Grigorian and Khudaverkian, 1970;Thomas and McLean, 1991;Pericic et al, 1996;Pesce et al, 2000). However, the precise mechanisms by which testosterone causes such bimodal effects on seizure susceptibility at the cellular level are unclear.…”

Section: Effect Of Testosterone On Seizure Susceptibilitymentioning

confidence: 99%

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Reddy¹

2008

Neurochemistry International

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Steroid hormones play a key role in the pathophysiology of several brain disorders. Testosterone modulates neuronal excitability, but the underlying mechanisms are obscure. There is emerging evidence that testosterone-derived "androgenic neurosteroids", 3α-androstanediol and 17β-estradiol, mediate the testosterone effects on neural excitability and seizure susceptibility. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17β-estradiol. Reduction of testosterone by 5α-reductase generates 5α-dihydrotestosterone, which is then converted to 3α-androstanediol, a powerful GABA A receptormodulating neurosteroid with anticonvulsant properties. Although the 3α-androstanediol is an emerging neurosteroid in the brain, there is no specific and sensitive assay for determination of 3α-androstanediol in biological samples. This article describes the development and validation of mass spectrometric assay of 3α-androstanediol, and the molecular mechanisms underlying the testosterone modulation of seizure susceptibility. A liquid chromatography-tandem mass spectrometry assay to measure 3α-androstanediol is validated with excellent linearity, specificity, sensitivity, and reproducibility. Testosterone modulation of seizure susceptibility is demonstrated to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. The proconvulsant effect of testosterone is associated with increases in plasma 17β-estradiol concentrations. The 5α-reduced metabolites of testosterone, 5α-dihydrotestosterone and 3α-androstanediol, had powerful anticonvulsant activity. Overall, the testosterone-derived neurosteroids 3α-androstanediol and 17β-estradiol could contribute to the net cellular actions of testosterone in the brain. Because 3α-androstanediol is a potent positive allosteric modulator of GABA A receptors, it could serve as an endogenous neuromodulator of neuronal excitability in men. The 3α-androstanediol assay is an important tool in this area because of the growing interest in the potential to use adjuvant aromatase inhibitor therapy to improve treatment of epilepsy.

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Castration alters susceptibility of male rats to specific seizures

Cited by 30 publications

References 7 publications

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA_A Receptors

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA_A Receptors

Role of hormones and neurosteroids in epileptogenesis

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

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Castration alters susceptibility of male rats to specific seizures

Cited by 30 publications

References 7 publications

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors

Role of hormones and neurosteroids in epileptogenesis

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

Contact Info

Product

Resources

About

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA_A Receptors

The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABA_A Receptors