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ProNGF, the precursor of mature nerve growth factor (NGF), is the most abundant form of NGF in the brain. ProNGF and mature NGF differ significantly in their receptor interaction properties and in their bioactivity. ProNGF increases markedly in the cortex of Alzheimer's disease (AD) brains and proNGF\NGF imbalance has been postulated to play a role in neurodegeneration. However, a direct proof for a causal link between increased proNGF and AD neurodegeneration is lacking. In order to evaluate the consequences of increased levels of proNGF in the postnatal brain, transgenic mice expressing a furin cleavage-resistant form of proNGF, under the control of the neuron-specific mouse Thy1.2 promoter, were derived and characterized. Different transgenic lines displayed a phenotypic gradient of neurodegenerative severity features. We focused the analysis on the two lines TgproNGF#3 and TgproNGF#72, which shared learning and memory impairments in behavioral tests, cholinergic deficit and increased Aβ-peptide immunoreactivity. In addition, TgproNGF#3 mice developed Aβ oligomer immunoreactivity, as well as late diffuse astrocytosis. Both TgproNGF lines also display electrophysiological alterations related to spontaneous epileptic-like events. The results provide direct evidence that alterations in the proNGF/NGF balance in the adult brain can be an upstream driver of neurodegeneration, contributing to a circular loop linking alterations of proNGF/NGF equilibrium to excitatory/inhibitory synaptic imbalance and amyloid precursor protein (APP) dysmetabolism.

Summary: We have investigated the comparative effects of estradiol benzoate (EB), the antiestrogenclomiphene citrate (CC), and the progesting medroxyprogesterone acetate (MPA) on seizures induced by systemic injection of kainic acid (15 mg/kg i.p.) in male and female rats. Subcutaneous administration for 10 days of EB (10 μg/kg) or high doses of CC (50 mg/kg) significantly potentiated kainate-induced seizures, with the effect being more pronounced in male animals. Doses of 2.5 mg/kg of CC potentiated kainate-induced seizures in male rats but were ineffective in female rats. Low doses of CC (0.5 mg/kg) exhibited a mild anticonvulsant effect in both sexes. repeated administration of MPA (2.5 mg/kg) partially protected female animals against kainate-induced seizures; in male animls, MPA induced a 30% increase in the seizure severity score, although the difference fro the score of control male rats was not significant. These data suggest hat sex steroids influence kainate-induced seizures in a sex-dependent manner and that the effects of the antiestrogen CC are dose dependent. This should be taken into account in view of a possible use of CC and MPA in hormonal therapy for seizure disorders. RESUME one a etudie les effets du benzoate d'oestradiol (EB), de l'antioestrogene citrate de clomifene (CC) et du progestatif acetate de medroxyprogesterone (MPA) sur les crises produites par l'injection d'acide kainique (15 mg/kg par voie intraperitoneale) a des rats mâles et femelles. L'administration sous-cutanee pendant 10 jours d'EB (10 μg/kg), ou des doses elevees de CC (50 mg/kg) potentialisent significativment les crises induites par l'acide kainique, cet effet etant plus prononce chez les mâles. Des doses de 2,5 mg/kg de CC potentialisent les crises induites par l'acide kainique chez les mâles, mais pas chez les femelles. De faibles doses de CC (0,5 mg/kg) ont un effet anticonvulsivant faible dans les 2 sexes. L'administration repetee de MPA (2,5 mg/kg) protege partiellement les femelles contre les crises induites par l'acide kainique. Chez les mâles, le MPA entraine une augmentation de 30% du score de severite des crises, quoique cependant la difference avec le score des mâles de controle ne soit pas significative (p < 0.05).Les donnees suggerent que les steroides sexuels influencent les crises induites par l'acide kainique d'une maniere dependant du sexe, et que les effets de l'antioestrogene CC sont dose-dependants. Cela doit etre pris en consideAration dans l'utilisation possible du CC et du MPA dans le traitement hormonal des epilepsies. RESUMEN En ratas hembras y machos hemos investigado los efectos comparativos del benzoato de estradiol (EB), del antiestrogeno citrato clomifeno (CC) y del progestin acetato medroxiprogesterona (MPA) sobre los ataques inducidos mediante la inyeccion sistomica de acido kainico (15 mg/kg, intraperitonealmente). La administracion subcutonea durante 10 dias de EB (10 μg/kg) o dosis altas de CC (50 mg/kg) potenciaron significativamente los ataque inducidos por el kainato, siendo este efecto mas pronunciado en los animales macho. Dosis de 2.5 mg/kg de CC potenciaron los ataques inducidos por el kainato en los machos pero no produjeron efectos en las hembras. Dosis bajas de CC (0.5 mg/kg) mostraron un efecto anticonvulsivo ligero en ambos sexos. La administracion repetida de MPA (2.5 mg/kg) protegieron parcialmente a las hembras de los ataques inducidos por el kainato; en los machos, el MPA produjo un 30% de incremento en la escala de severidad de los ataques aunque la diferencia con la escala de los machos control no fue significativa (p > 0.05). Toda esta informacion sugiere que los esteriodes, segun el sexo, influencian los ataques inducidos por el kainato de un modo sexo-dependiente y que los efectos del antiestrogeno CC son dosis-dependientes. Estos datos podrian ser tenidos en cuenta en vista de una posible utilizacion del CC y del MPA en la terapeutica hormonal de los trastornos convulsivos. Wir untersuchten die Wirkungen von Oestradiolbenzoat (EB), dem Antioestrogen Clomiphencitrat (CC) und dem Progestinmedroxyprogesteronacetat (MPA) auf Anfalle, die durch die systemische Injektion von Kainsaure (15 mg/kg intraperitoneal) bei mannlichen und weiblichen Ratten hervorgerufen wurden, 10-tagige subkutane Anwendung von EB (10 ug/kg) oder hohe Dosen von CC (50 mg/kg) potenzierten in signifikanter Weise Kain-induzierte Anfalle. Diese Wirkung trat besonders bei mannlichen Tieren auf. Dosen von 2, 5 mg/kg CC potenzierte Kainat-induzierte Anfalle bei maannlichen aber nicht bei weiblichen Ratten. Niedrige Dosen von CC (0, 5 mg/kg) zeigten eine milde antikonvulsive Wirkung bei beiden Geschlechtern. Die wiederholte Anwendung von MPS (2, 5 mg/kg) schutzte weibliche Tiere partiell gegen Kainatinduzierte Anfalle. Bei mannlichen Ratten bewirkte MPA eine 30-prozentige Zunahme der Schwere der Anfalle, obwohl der Unterschied zu dem Score der Kontrolltiere nicht signifikant war (p > 0,05). Diese Ergebnisse legen nahe, daβ Geschlechtssteroide Kainat-induzierte Anfalle in einer geschlechtsabhangigen Art und Weise beeinflussen und daβ die Wirkungen des Antioestrogens CC dosisabhangig sind. Das muβ bei einer moglichen Anwendung von CC und MPA in der Hormontherapie von Anfallsleiden [berucksichtigt werden].