SEXUAL DIMORPHISM IN SEIZURE CONTROL

癫痫发作控制中的性二态性

• 批准号: 6126339
• 负责人: JANA VELISKOVA
• 金额: $ 11.86万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6126339
• 关键词: GABA receptor; autoradiography; developmental neurobiology; early experience; embryo /fetus; embryo /fetus pharmacology; epilepsy; gender difference; hormone regulation /control mechanism; laboratory rat; mammalian embryology; muscimol; neuropharmacology; neurotransmitter agonist; neurotransmitter antagonist; substantia nigra; testosterone

DESCRIPTION: Steroid hormonal regulation is critical for normal brain development and may play an important role in human seizure disorders. The substantia nigra pars reticulata (SNR) is one of the structures controlling the spread of seizure activity via its GABAergic neurotransmission especially through GABAA receptors. The SNR is functionally subdivided into anterior and posterior regions which mediate opposing effects of muscimol (a GABAA receptor agonist) on fluorothyl seizures. Muscimol infusions in the SNRanterior produce anticonvulsant effects, while similar infusions in the SNRposterior produce proconvulsant effects. Preliminary data show that the functional maturation of these two SNR regions may be under gonadal steroid hormonal control. In neonatally castrated m ale rats there is accelerated maturation of the "anticonvulsant" SNRanterior. Neonatal castration does not influence the emergence of the "proconvulsant" SNR region. Furthermore, in female rats there is no functional segregation of the SNR because muscimol infusions produce anticonvulsant effects irrespective to injection site. Therefore, the presence of testosterone early in life may be responsible for the functional segregation of the SNR. The following hypotheses will be tested: In male rats, early postnatal depletion of testosterone accelerates the development of the "anticonvulsant" SNRanterior region. In male rats, the emergence of the "proconvulsant" SNRposterior region is independent of early postnatal testosterone. The two SNR regions in neonatally castrated rats have similar features as the two SNR regions in normal male rats (the term features denotes responsivity to GABAergic agents and output networks). Lack of prenatal testosterone leads to the female type of the SNR with only one GABAA sensitive SNR region. The female SNR may have similar features with the mature male "anticonvulsant" SNRanterior. The prenatal testosterone surge is responsible for the development of the "proconvulsant" SNR region. Methods include early postnatal castration and hormone replacements, localized infusions of GABAA agonists and antagonists, flurothyl seizure testing and [14C] deoxyglucose autoradiography. Rats of both sexes and various ages will be used. These studies may lead to the development of new antiepileptic treatments that take into the account sexual age-related differences.

描述：类固醇激素调节对正常大脑至关重要。 并可能在人类癫痫发作障碍中发挥重要作用。这个 黑质网状部(SNR)是其中的一种控制结构 癫痫发作活动的GABA能神经传递 尤其是通过GABAA受体。SNR在功能上细分为 前部和后部区域调节蝇醇(A)的相反作用 GABAA受体激动剂)。麝香酚在人体内的输注 SNR前体产生抗惊厥作用，而类似的输液在 SNR后部产生惊厥前效应。初步数据显示， 这两个SNR区的功能成熟可能是在性腺类固醇的作用下实现的 荷尔蒙控制。在新生去势的雌性大鼠中， “抗惊厥剂”SNR的成熟。新生儿阉割会 不影响“前惊厥”信噪比区域的出现。此外， 在雌性大鼠中，SNR没有功能性分离，因为 麝香酚输液无论注射与否都能产生抗惊厥作用 地点。因此，生命早期睾丸激素的存在可能是 负责信噪比的功能隔离。以下是 假说将得到检验：在雄性大鼠中，出生后早期脑组织中的 睾酮加速抗惊厥药SNR前部的发育 区域。在雄性大鼠中，“前惊厥”SNR后部的出现 该区域不依赖于出生后早期的睾丸素。两个信噪比区域 新生去势大鼠脑内两个SNR区具有相似的特征 正常雄性大鼠(术语特征表示对GABA能药物的反应性 和输出网络)。产前缺乏睾丸素会导致女性 只有一个GABAA敏感SNR区域的SNR类型。女性的信噪比 可能与成熟的男性“抗惊厥剂”SNR具有相似的特征。 孕期睾丸素的激增是导致 “惊厥前”信噪比区域。方法包括出生后早期阉割和 激素替代，局部输注GABAA激动剂和拮抗剂， 氟乙基癫痫试验和[14C]脱氧葡萄糖放射自显影。的大鼠 性别和不同年龄的人都将被使用。这些研究可能会导致 考虑到这一点的新的抗癫痫治疗的发展 性别与年龄相关的差异。