@misc{reddy_2008, title={Mass spectrometric assay and physiological-pharmacological activity of androgenic neurosteroids}, volume={52}, number={4-5}, journal={Neurochemistry International}, author={Reddy, D. S.}, year={2008}, pages={541–553} }
 @article{reddy_zeng_2007, title={Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor a and B subtypes}, volume={29}, DOI={10.1358/mf.2007.29,10.1147766}, abstractNote={Progesterone affects the function of the brain by multiple mechanisms. The physiological effects of progesterone are mediated by the interaction of the hormone with progesterone receptors (PRs), which are widely expressed in the hypothalamus, hippocampus and limbic areas. The PR is composed of two protein isoforms, PR-A and PR-B, which are expressed from a single PR gene. In addition, progesterone influences neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABA(A) receptors. However, the role of PRs in the sedative-hypnotic action of neurosteroids is unclear. In this study, PR knockout (PRKO) mice were used as model to study the sedative-anesthetic actions of the progesterone-derived neurosteroid allopregnanolone and the noncompetitive NMDA receptor antagonist ketamine. Mice were confirmed to be PR deficient by genotyping and immunohistochemistry of PR expression in the brain. Anesthetic potency was evaluated by the loss of the righting reflex paradigm. Allopregnanolone-induced anesthetic activity was similar in PRKO mice and their wild-type littermates, suggesting that PRs are not involved in the anesthetic response to allopregnanolone. However, the noncompetitive NMDA receptor antagonist ketamine has significantly reduced anesthetic potency in PRKO mice, suggesting a possible developmental plasticity of glutamate receptors. There was no marked gender-related difference to ketamine response in both genotypes. In conclusion, these results suggest that the neurosteroid allopregnanolone and ketamine produce differential anesthetic response in mice lacking PRs.}, number={10}, journal={Methods and Findings in Experimental and Clinical Pharmacology}, author={Reddy, D. S. and Zeng, Y. C.}, year={2007}, pages={659–664} }
 @article{rao_hattiangady_reddy_shetty_2006, title={Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy}, volume={83}, ISSN={["1097-4547"]}, DOI={10.1002/jnr.20802}, abstractNote={Abstract}, number={6}, journal={JOURNAL OF NEUROSCIENCE RESEARCH}, author={Rao, MS and Hattiangady, B and Reddy, DS and Shetty, AK}, year={2006}, month={May}, pages={1088–1105} }
 @article{reddy_2006, title={Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions}, volume={138}, ISSN={["1873-7544"]}, DOI={10.1016/j.neuroscience.2005.10.016}, abstractNote={Stress increases plasma and brain concentrations of corticosteroids and neuroactive steroids. Cortisol is the most important stress hormone in the hypothalamic pituitary adrenocortical system. However, significant amounts of the mineralocorticoid deoxycorticosterone are also released during stress. Deoxycorticosterone undergoes biotransformation to allotetrahydrodeoxycorticosterone, a neuroactive steroid with anxiolytic and anticonvulsant properties. Our studies indicate that the anticonvulsant activity of deoxycorticosterone is mediated by its conversion to allotetrahydrodeoxycorticosterone, which is a potent positive allosteric modulator of GABAA receptors. Although the role of allotetrahydrodeoxycorticosterone within the brain is undefined, recent studies indicate that stress induces increases in allotetrahydrodeoxycorticosterone to levels that can activate GABAA receptors. These results might have significant implications for human stress-sensitive conditions such as epilepsy, panic disorder, post-traumatic stress disorder, and major depression. In epilepsy, a role for adrenal allotetrahydrodeoxycorticosterone in seizure susceptibility has been suggested. Recent preclinical studies indicate a role of neuroactive steroids in ethanol actions. Although these studies provide a better understanding of the role of allotetrahydrodeoxycorticosterone and related neuroactive steroids in acute stress, further studies are clearly warranted to ascertain the specific role of neuroactive steroids in the pathophysiology of chronic stress and related brain conditions.}, number={3}, journal={NEUROSCIENCE}, author={Reddy, DS}, year={2006}, pages={911–920} }
 @article{reddy_venkatarangan_chien_ramu_2005, title={A high-performance liquid chromatography-tandem mass spectrometry assay of the androgenic neurosteroid 3 alpha-androstanediol (5 alpha-androstane-3 alpha,17 beta-diol) in plasma}, volume={70}, ISSN={["0039-128X"]}, DOI={10.1016/j.steroids.2005.05.007}, abstractNote={The testosterone metabolite 3alpha-androstanediol (5alpha-androstane-3alpha,17-diol) is a potential GABA(A) receptor-modulating neurosteroid with anticonvulsant properties and hence could act as a key neuromodulator in the central nervous system. However, there is no specific and sensitive assay for quantitative determination of the androgenic neurosteroid 3alpha-androstanediol in biological samples. We have established a liquid chromatography-tandem mass spectrometry (LC-MS-MS) assay to measure 3alpha-androstanediol in rat plasma. Standard 3alpha-androstanediol added to rat plasma has been successfully analysed with excellent linearity, specificity, sensitivity, and reproducibility. The sensitivity of the method was < 10 ng/ml with a detection limit of 2 ng/ml (6.8 nmol/l) and a linear range of 10-2000 ng/ml. The method was used for the analysis of testosterone-induced increase in plasma 3alpha-androstanediol levels in rats. Testosterone produced a dose-dependent elevation in plasma 3alpha-androstanediol, which was almost completely prevented by pretreatment with the 5alpha-reductase inhibitor finasteride, indicating that 3alpha-androstanediol is synthesized from testosterone via a 5alpha-reductase pathway. This LC-MS-MS method allows accurate, high-throughput analysis of 3alpha-androstanediol in small amounts (200 microl) of plasma and possibly other biological samples.}, number={13}, journal={STEROIDS}, author={Reddy, DS and Venkatarangan, L and Chien, B and Ramu, K}, year={2005}, month={Dec}, pages={879–885} }
 @article{reddy_apanites_2005, title={Anesthetic effects of progesterone are undiminished in progesterone receptor knockout mice}, volume={1033}, ISSN={["1872-6240"]}, DOI={10.1016/j.brainres.2004.11.026}, abstractNote={Progesterone has sedative and anesthetic effects but the underlying molecular mechanisms remain unclear. The two possible mechanisms by which progesterone affects the function of the brain include binding to intracellular progesterone receptors (PR) and metabolism to GABAA receptor-modulating neurosteroids. In this study, PR knockout (PRKO) mice were used as model to study the role of PRs in the anesthetic activity of progesterone. The progesterone-induced anesthetic activity was undiminished in female PRKO mice (ED50, 172 mg/kg) as compared to their wild-type littermates (ED50, 167 mg/kg). The progesterone-induced anesthetic activity was highly correlated with increased plasma allopregnanolone levels. Pretreatment of PRKO mice with the 5α-reductase inhibitor finasteride significantly reduced the progesterone-induced anesthetic activity. Allopregnanolone also evoked dose-dependent anesthetic activity in PRKO mice, which was similar to those of wild-type mice. Thus, the anesthetic activity of progesterone is not mediated by its interaction with PRs. The neurosteroid allopregnanolone partially mediates the anesthetic activity of progesterone by potentiation of GABAA receptor function.}, number={1}, journal={BRAIN RESEARCH}, author={Reddy, DS and Apanites, LA}, year={2005}, month={Feb}, pages={96–101} }
 @article{reddy_bw o'malley_rogawski_2005, title={Anxiolytic activity of progesterone in progesterone receptor knockout mice}, volume={48}, ISSN={["1873-7064"]}, DOI={10.1016/j.neuropharm.2004.09.002}, abstractNote={Progesterone is an anxiolytic steroid that could play a role in the regulation of anxiety in women. However, the mechanism by which progesterone decreases anxiety is incompletely understood. Progesterone affects the function of the brain by two distinct mechanisms. Progesterone regulates reproductive behavior by activating intracellular progesterone receptors (PRs). In addition, progesterone is believed to influence neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABAA receptors. The extent to which the anxiolytic action of progesterone requires PRs is uncertain. In this study, we utilized PR knockout (PRKO) mice bearing a targeted null mutation of the PR gene that abrogates the function of both PR-A and PR-B subtypes to determine the requirement for PRs in the anxiolytic actions of progesterone. The absence of PR receptor protein expression in PRKO brain was confirmed by immunocytochemistry. In PRKO mice and their isogenic wild-type (WT) littermates, progesterone administration was associated with a dose-dependent rise in plasma allopregnanolone concentrations and corresponding anxiolytic effects in the elevated plus maze test. PRKO mice exhibited a greater anxiolytic response than WT animals although the allopregnanolone levels were similar in the two genotypes. Allopregnanolone also exhibited anxiolytic effects, but the magnitude of the response was similar in both genotypes. Pretreatment of PRKO mice with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone, completely prevented the anxiolytic activity of progesterone, but had no effect on the response to allopregnanolone, demonstrating that allopregnanolone (or other 5alpha-reduced metabolites of progesterone) accounts for the response to the parent steroid hormone. These results provide direct evidence that the anxiolytic action of progesterone does not require PRs. However, PR activation by progesterone may influence the anxiolytic response since PRKO mice were more sensitive to progesterone.}, number={1}, journal={NEUROPHARMACOLOGY}, author={Reddy, DS and BW O'Malley and Rogawski, MA}, year={2005}, month={Jan}, pages={14–24} }
 @article{reddy_castaneda_bw o'malley_rogawski_2004, title={Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice}, volume={310}, ISSN={["1521-0103"]}, DOI={10.1124/jpet.104.065268}, abstractNote={Many of the biological actions of progesterone are mediated through the progesterone receptor (PR), a nuclear transcription factor. Progesterone is well recognized to protect against seizures in animal models. Although this activity has been attributed to the progesterone metabolite allopregnanolone, a GABAA receptor-modulating neurosteroid with anticonvulsant properties, PRs could also play a role. Here, we used PR knockout (PRKO-/-) mice bearing a targeted deletion of the PR gene that eliminates both isoforms of the PR to investigate the contribution of the PR to the anticonvulsant activity of progesterone. The protective activity of progesterone was examined in female and male homozygous PRKO mice and isogenic wild-type controls in the pentylenetetrazol (PTZ), maximal electroshock, and amygdala-kindling seizure models. In all three models, the anticonvulsant potency of progesterone was undiminished in PRKO mice compared with control mice. On the contrary, there was a substantial increase in the anticonvulsant potency of progesterone in the PTZ and kindling models. The antiseizure activity of progesterone in PRKO mice was reversed by pretreatment with finasteride, a 5α-reductase inhibitor that blocks the metabolism of progesterone to allopregnanolone. Unlike progesterone, the neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone exhibited comparable anticonvulsant potency in PRKO and wild-type mice. The basis for the heightened progesterone responsiveness of PRKO mice is not attributable to pharmacokinetic factors, because the plasma allopregnanolone levels achieved after progesterone administration were not greater in the PRKO mice. These studies provide strong evidence that the PR is not required for the antiseizure effects of progesterone, which mainly occurs through its conversion to the neurosteroid allopregnanolone.}, number={1}, journal={JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS}, author={Reddy, DS and Castaneda, DC and BW O'Malley and Rogawski, MA}, year={2004}, month={Jul}, pages={230–239} }
 @article{reddy_2004, title={Anticonvulsant activity of the testosterone-derived neurosteroid 3 alpha-androstanediol}, volume={15}, DOI={10.1097/01.wnr.0000113064.17279.32}, number={3}, journal={NeuroReport}, author={Reddy, D. S.}, year={2004}, pages={515–518} }
 @misc{reddy_woodward_2004, title={Ganaxolone: a prospective overview}, volume={29}, ISSN={["2013-0368"]}, DOI={10.1358/dof.2004.029.03.793135}, abstractNote={Ganaxolone is a synthetic analogue of the endogenous neurosteroid allopregnanolone, a metabolite of progesterone. Like allopregnanoiene, ganaxolone is a potent positive allosteric modulator of aminobutyric acid type A (GABA) receptors. Ganaxolone has robust anticonvuisant effects in a variety of animal models of epilepsy, is orally active and lacks hormonal side effects. Unlike diazepam, anticonvulsant tolerance does not develop to ganaxolone following chronic therapy. Recent predlinical studies suggest that ganaxolone is a particularly promising treatment for catamenial epilepsy. a menstrual cycle-related seizure disorder characterized by an increase in seizures at the time or menstruation. Preliminary evidence of the efficacy of ganaxolone in the treatment of epilopsy is encouraging. In general, ganaxolone has a favorable safety profile. The most frequentiy reported side effect is somnolence, which occurs with an acceptable therapeutic index. Ganaxoione has demonstrated significant clinical efficacy in suppressing complex partial seizures. Two open-label trials of ganaxolone in infantile spasms have been reported with indications of efficacy in both cases, Ganaxolone has enhanced potency in an animal model of catamenial epilepsy, and there is promising preliminary evidence for the efficacy of ganaxolone 'pulse therapy' for catamenial selzures in women. In addition, since premenstrual syndrome (PMS) is associated with allopregnanolone deficiency, ganaxolone may also have utility in the management of PMS. As a novel GABA a receptor modulator with unique, broad-spectrum protective efficacy, ganaxolone may have additional therapeutic potential in alcohol and cocaine withdrawal seizures, as well as in the treatment of anxiety and other mood disorders.}, number={3}, journal={DRUGS OF THE FUTURE}, author={Reddy, DS and Woodward, R}, year={2004}, month={Mar}, pages={227–242} }
 @misc{reddy_2004, title={Pharmacology of catamenial epilepsy}, volume={26}, number={7}, journal={Methods and Findings in Experimental and Clinical Pharmacology}, author={Reddy, D. S.}, year={2004}, pages={547–561} }
 @misc{reddy_2004, title={Role of neurosteroids in catamenial epilepsy}, volume={62}, ISSN={["1872-6844"]}, DOI={10.1016/j.eplepsyres.2004.09.003}, abstractNote={Catamenial epilepsy is a menstrual cycle-related seizure disorder that affects up to 70% of women with epilepsy. Catamenial epilepsy is characterized by an increase in seizures during particular phases of the menstrual cycle. Three distinct patterns of catamenial epilepsy – perimenstrual, periovulatory, and inadequate luteal phase – have been described. Currently, there is no specific treatment for catamenial epilepsy. The molecular mechanisms involved in the pathophysiology of catamenial epilepsy are not well understood. Recent studies suggest that cyclical changes of ovarian hormones estrogens (proconvulsant) and progesterone (anticonvulsant) appear to play a key role in the genesis of catamenial seizures. Progesterone reduces seizure susceptibility partly through conversion to neurosteroids such as allopregnanolone, which enhances GABAA receptor function and thereby inhibits neuronal excitability. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy has proven effective in women with epilepsy. Moreover, neurosteroids have been shown to be very effective inhibitors of catamenial seizures in animal models. Thus, synthetic neuroactive steroids, such as ganaxolone, which are orally active and devoid of hormonal side effects, represent a novel treatment strategy for catamenial epilepsy. However, their clinical efficacy in catamenial epilepsy has yet to be explored. A greater understanding of the molecular mechanisms is clearly needed for designing effective treatment and prevention strategies of catamenial epilepsy in women at risk.}, number={2-3}, journal={EPILEPSY RESEARCH}, author={Reddy, DS}, year={2004}, month={Dec}, pages={99–118} }
 @article{reddy_2004, title={Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3 alpha-androstanediol and 17 beta-estradiol}, volume={129}, ISSN={["1873-7544"]}, DOI={10.1016/j.neuroscience.2004.08.002}, abstractNote={Testosterone modulates seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, testosterone modulation of seizure susceptibility is hypothesized 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. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17beta-estradiol. Reduction of testosterone by 5alpha-reductase generates 5alpha-dihydrotestosterone (DHT), which is then converted to 3alpha-androstanediol (3alpha-Diol), a powerful GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Systemic doses of testosterone decreased seizure threshold in rats and increased the incidence and severity of pentylenetetrazol (PTZ)-induced seizures in mice. These proconvulsant effects of testosterone were associated with increases in plasma 17beta-estradiol and 3alpha-Diol concentrations. Pretreatment with letrozole, an aromatase inhibitor that blocks the conversion of testosterone to 17beta-estradiol, significantly inhibited testosterone-induced exacerbation of seizures. The 5alpha-reductase inhibitor finasteride significantly reduced 3alpha-Diol levels and also blocked letrozole's ability to inhibit the proconvulsant effects of testosterone. The 5alpha-reduced metabolites of testosterone, DHT and 3alpha-Diol, had powerful anticonvulsant activity in the PTZ test. Letrozole or finasteride had no effect on seizure protection by DHT and 3alpha-Diol, but indomethacin partially reversed DHT actions. 3alpha-Diol but not 3beta-androstanediol, a GABA(A) receptor-inactive stereoisomer, suppressed 4-aminopyridine-induced spontaneous epileptiform bursting in rat hippocampal slices. Thus, testosterone-derived neurosteroids 3alpha-Diol and 17beta-estradiol could contribute to the net cellular actions of testosterone on neural excitability and seizure susceptibility.}, number={1}, journal={NEUROSCIENCE}, author={Reddy, DS}, year={2004}, pages={195–207} }
 @article{reddy_2003, title={Is there a physiological role for the neurosteroid THDOC in stress-sensitive conditions?}, volume={24}, ISSN={["1873-3735"]}, DOI={10.1016/S0165-6147(03)00023-3}, abstractNote={Endogenous neurosteroids affect brain excitability during physiological states such as pregnancy and the menstrual cycle, and during conditions of acute and chronic stress. The neurosteroid allotetrahydrodeoxycorticosterone (THDOC) is an allosteric modulator of the GABA(A) receptor. Although the role of THDOC within the brain is undefined, recent studies indicate that stress induces THDOC to levels that can activate GABA(A) receptors. These results might have significant implications for human stress-sensitive conditions such as epilepsy, post-traumatic stress disorder and depression.}, number={3}, journal={TRENDS IN PHARMACOLOGICAL SCIENCES}, author={Reddy, DS}, year={2003}, month={Mar}, pages={103–106} }
 @misc{reddy_2002, title={Newer gabaergic agents for pharmacotherapy of infantile spasms}, volume={38}, ISSN={["1699-4019"]}, DOI={10.1358/dot.2002.38.10.820139}, abstractNote={Infantile spasms is an age-specific epileptic syndrome in infants and young children. Although the exact mechanism is unknown, adrenocorticotrophic hormone (ACTH) has been the mainstay for the therapeutic management of infantile spasms and other developmental epilepsies. Clinical benefits of ACTH in infantile spasms could partially relate to its stimulatory effects on the release of adrenocorticosteroids and neurosteroids. Glucocorticoids, pyridoxine and ketogenic diet therapy have all been used for the treatment of refractory infantile spasms. Recent studies indicate that several newer anticonvulsant agents, which are positive allosteric modulators of GABA(A) receptors, are as effective as ACTH in acutely controlling infantile spasms. The efficacy of agents that enhance GABA-mediated inhibition (such as vigabatrin and benzodiazepines) for rapid and complete abolition of infantile spasms has been demonstrated in several clinical studies. Ganaxolone, a novel neuroactive steroid has, however, demonstrated outstanding efficacy and better tolerability in children with intractable infantile spasms. Zonisamide, topiramate, deoxycorticosterone and neurosteroids are emerging as effective treatment approaches. These new antiepileptic drugs represent a potential nonhormonal approach for infantile spasms, but additional studies are needed to verify their efficacy and tolerability. Future studies will hopefully identify rational antiseizure drugs that not only control infantile spasms but also abrogate its risk on the development of the brain.}, number={10}, journal={DRUGS OF TODAY}, author={Reddy, DS}, year={2002}, month={Oct}, pages={657–675} }
 @misc{reddy_2002, title={The clinical potentials of endogenous neurosteroids}, volume={38}, ISSN={["1699-4019"]}, DOI={10.1358/dot.2002.38.7.820115}, abstractNote={Stress increases plasma and brain concentrations of the neurosteroids allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC), which can have potent effects on GABAA receptors in the brain. Blockade of the formation of neurosteroids prevents specific biochemical and behavioral effects of stress, suggesting that those effects are dependent upon the actions of GABA(A)-receptor active neurosteroids. Recent investigations provide a better understanding of the role of endogenous neurosteroids in normal neuronal development and in the pathophysiology of brain disorders. Physiological neurosteroid fluctuations have potential implications for stress-sensitive neurological conditions such as epilepsy, infantile spasms, as well as psychiatric disorders such as schizophrenia, posttraumatic stress disorder and depression. Future studies may provide important new evidence that may not only explain acute actions of stress, but also reveal the clinical importance of neurosteroid mechanisms during chronic stress.}, number={7}, journal={DRUGS OF TODAY}, author={Reddy, DS}, year={2002}, month={Jul}, pages={465–485} }