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The major contribution of this work is the isolation of a neuroprotective compound referred to as 2-amino-5-ureidopentanamide (FrPbAII) (M r ϭ 174) from Parawixia bistriata spider venom and an investigation of its mode of action. FrPbAII inhibits synaptosomal GABA uptake in a dose-dependent manner and probably does not act on Na ϩ , K ϩ , and Ca 2ϩ channels, GABA B receptors, or ␥-aminobutyrate:␣-ketoglutarate aminotransferase enzyme; therefore, it is not directly dependent on these structures for its action. Direct increase of GABA release and reverse transport are also ruled out as mechanisms of FrPbAII activities as well as unspecific actions on pore membrane formation. Moreover, FrPbAII is selective for GABA and glycine transporters, having slight or no effect on monoamines or glutamate transporters. According to our experimental glaucoma data in rat retina, FrPbAII is able to cross the blood-retina barrier and promote effective protection of retinal layers submitted to ischemic conditions. These studies are of relevance by providing a better understanding of neurochemical mechanisms involved in brain function and for possible development of new neuropharmacological and therapeutic tools.

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The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids.

1. The GABAergic neurotransmission has been implicated in the modulation of many neural networks in forebrain, midbrain and hindbrain, as well as, in several neurological disorders. 2. The complete comprehension of GABA system neurochemical properties and the search for approaches in identifying new targets for the treatment of neural diseases related to GABAergic pathway are of the extreme relevance. 3. The present review will be focused on the pharmacology and biochemistry of the GABA metabolism, GABA receptors and transporters. In addition, the pathological and psychobiological implications related to GABAergic neurotransmission will be considered.

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Kisspeptin is the most potent stimulator of LH release. There are two kisspeptin neuronal populations in the rodent brain: in the anteroventral periventricular nucleus (AVPV) and in the arcuate nucleus. The arcuate neurons coexpress kisspeptin, neurokinin B, and dynorphin and are called KNDy neurons. Because estradiol increases kisspeptin expression in the AVPV whereas it inhibits KNDy neurons, AVPV and KNDy neurons have been postulated to mediate the positive and negative feedback effects of estradiol on LH secretion, respectively. Yet the role of KNDy neurons during the positive feedback is not clear. In this study, ovariectomized rats were microinjected bilaterally into the arcuate nucleus with a saporin-conjugated neurokinin B receptor agonist for targeted ablation of approximately 70% of KNDy neurons. In oil-treated animals, ablation of KNDy neurons impaired the rise in LH after ovariectomy and kisspeptin content in both populations. In estradiol-treated animals, KNDy ablation did not influence the negative feedback of steroids during the morning. Surprisingly, KNDy ablation increased the steroid-induced LH surges, accompanied by an increase of kisspeptin content in the AVPV. This increase seems to be due to lack of dynorphin input from KNDy neurons to the AVPV as the following: 1) microinjections of a dynorphin antagonist into the AVPV significantly increased the LH surge in estradiol-treated rats, similar to KNDy ablation, and 2) intra-AVPV microinjections of dynorphin in KNDy-ablated rats restored LH surge levels. Our results suggest that KNDy neurons provide inhibition to AVPV kisspeptin neurons through dynorphin and thus regulate the amplitude of the steroid-induced LH surges.

During the transition to menopause, women experience a variety of physical and psychological symptoms that are directly or indirectly linked to changes in hormone secretion. Establishing animal models with intact ovaries is essential for understanding these interactions and finding new therapeutic targets. In this study, we assessed the endocrine profile, as well as the estrous cycle, in the 4-vinylcyclohexene diepoxide (VCD)-induced follicular depletion rat model in 10-day intervals over 1 month to accurately establish the best period for studies of the transition period. Twenty-eight-day-old female rats were injected daily with VCD or oil s.c. for 15 days and euthanized in the diestrus phase approximately 70, 80, 90 and 100 days after the onset of treatment. The percentage of rats showing irregular cycles and the plasma level of FSH increased only in the 100-day VCD group. Plasma anti-Müllerian hormone (AMH) and progesterone were lower in all VCD groups compared to control groups, while estradiol remained unchanged or higher. As in control groups, dihydrotestosterone (DHT) progressively decreased in the 70-90-day VCD groups; however, it was followed by a sharp increase only in the 100-day VCD group. No changes were found in plasma corticosterone, prolactin, thyroid hormones or luteinizing hormone. Based on the estrous cycle and endocrine profile, we conclude that 1) the time window from 70 to 100 days is suitable to study a perimenopause-like state in this model, and 2) regular cycles with low progesterone and AMH and normal FSH can be used as markers of the early/mid-transition period, whereas irregular cycles associated with higher FSH and DHT can be used as markers of the late transition period to estropause.