Effects of GABAB receptor positive allosteric modulator BHF177 and IRS-1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway.

The present study was conducted to determine the effects of the γ-aminobutyric acid B (GABAB ) receptor positive allosteric modulator BHF177 on refractory epilepsy (RE). An RE rat model was initially established via treatment with lithium-pilocarpine. The RE rats were then treated with BHF177 or the GABAB receptor antagonist CGP46381, followed by recording of their seizure rate and assessment of their spatial learning in the Morris water maze test. Treatment of BHF177 reduced the seizure intensity, whereas this effect was revered upoj treatment with CGP46381. Immunohistochemistry revealed that BHF177 treatment diminished P-glycoprotein (P-gp) expression in the hippocampal tissues of RE rats. Next, we found that BHF177 activated GABAB receptor, resulting in upregulated expression of insulin receptor substrate 1 (IRS-1) and PI3K, as well as antiapoptotic factors (Bcl-2 and mTOR), along with suppression of the apoptosis factors Bax and cleaved caspase-3 in the hippocampal tissues. Further, activation of GABAB receptors by BHF177 alleviated the inflammatory response in hippocampal tissues of RE rats, as evidenced by reduced VCAM-1, ICAM-1, and tumor necrosis factor-α levels. Next, we treated primary cultured rat hippocampal neurons with BHF177 and the IRS-1 selective inhibitor NT157. BHF177 inhibited hippocampal apoptosis in rat hippocampal neurons by regulating the IRS-1/PI3K/Akt axis through crosstalk between GABAB and insulin-like growth factor-1 receptors. Collectively, our findings indicate that the BHF177 inhibited neuron apoptosis, thus protecting against RE through the IRS-1/PI3K/Akt axis, which may present a new therapeutic channel for RE.

Papel de los receptores Gaba-a en el tratamiento del insomnio: eszopiclona. Revisón de su eficacia y seguridad en adultos y ancianos / The role of nonbenzodiazepine Gaba-a agonist ininsomnia treatment: eszopiclone, efficacy and safety review in adults and the elderly

Eszopiclona es un nuevo hipnótico para el tratamiento del insomnio, especialmente desarrollado en el insomnio crónico que requiere tratamiento a largo plazo. Eszopiclona pertenece al grupo de los hipnóticos no-benzodiacepínico agonistas del receptor GABA-A y constituye el isómero (S) del compuesto racémico zopiclona. Está comercializado en Estados Unidos desde abril de 2005 (Sepracor) y actualmente está en proceso de registro en Europa (Sepracor/GlaxoSmithKline). Eszopiclona ha demostrado su eficacia no sólo al mejorar la latencia del sueño, sino también en el mantenimiento del mismo, sin provocar síntomas residuales al día siguiente, en comparación con placebo, tanto en adultos como en ancianos, en un amplio programa de desarrollo clínico (11 ensayos clínicos). Es el primer hipnótico que ha demostrado eficacia en el tratamiento a largo plazo del insomnio en dos estudios de 6 meses de duración, controlados con placebo, en los que también se evidenció que eszopiclona, a dosis de 3mg, es bien tolerado. No se ha observado el desarrollo de tolerancia en un estudio de 12 meses a dosis diarias de 3mg. La retirada de eszopiclona no evidenció insomnio de rebote significativo o síntomas intensos de discontinuación. Igualmente se ha demostrado eficacia en estudios en pacientes con insomnio comórbido con depresión mayor, trastorno de ansiedad generalizada (TAG), menopausia y artritis reumatoide/ dolor. Eszopiclona a dosis de 3 mg, en adultos, y 2 mg, en ancianos, ha demostrado ser un hipnótico no-benzodiacepínico eficaz y bien tolerado en pacientes con insomnio. Mejora significativamente los parámetros del sueño y el funcionamiento diario, sin evidencia de tolerancia en estudios a largo plazo. Eszopiclona constituye una opción terapéutica útil en el tratamiento del insomnio ya sea primario o comórbido, a corto o largo plazo (AU)

Eszopiclone was developed as a new hypnotic treatment for insomnia, including chronic insomnia that requires longterm treatment. Eszopiclone belongs to the nonbenzodiazepine GABA-A agonist group. It is the (S)- enantiomer of racemic zopliclone developed by Sepracor. Eszopiclone is approved in US since April 2005 and is undergoing approval process in Europe (Sepracor/GlaxoSmithKline). Eszopiclone, in a wide clinical development plan including 11 well designed clinical trials, has demonstrated its efficacy by improving sleep latency as well as improving sleep maintenance, among others sleep parameters, without next-day residual effects, compared to placebo, in adults and the elderly. It is the first hypnotic that has demonstrated efficacy in the long-term use up to 6 months, in two placebo-controlled trials, and it is well tolerated at a 3 mg dose. There was no evidence of development of tolerance during 12 months of treatment with every day 3mg dose. On discontinuation of eszopiclone, there was no evidence of significant rebound insomnia or serious withdrawal effects. Also efficacy has been demonstrated in insomnia comorbid with conditions such as major depression, generalized anxiety disorder, menopausal transition and rheumatoid arthritis. Eszopiclone, at a 3 mg dose in adults and 2 mg in the elderly, has demonstrated to be an effective and well tolerated nonbenzodiazepine hypnotic for insomnia patients. It significantly improved sleep parameters and daytime functioning, with no evidence of tolerance in long-term studies. Eszopiclone is a useful therapeutic option in the management of primary or comorbid insomnia, at short and long-term (AU)

Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors.

Family C of G-protein coupled receptors (GPCRs) from humans is constituted by eight metabotropic glutamate (mGlu(1-8)) receptors, two heterodimeric gamma-aminobutyric acid(B) (GABA(B)) receptors, a calcium-sensing receptor (CaR), three taste (T1R) receptors, a promiscuous L-alpha-amino acid receptor (GPRC6A), and five orphan receptors. Aside from the orphan receptors, the family C GPCRs are characterised by a large amino-terminal domain, which bind the endogenous orthosteric agonists. Recently, a number of allosteric modulators binding to the seven transmembrane domains of the receptors have also been reported. Family C GPCRs regulate a number of important physiological functions and are thus intensively pursued as drug targets. So far, two drugs acting at family C receptors (the GABA(B) agonist baclofen and the positive allosteric CaR modulator cinacalcet) have been marketed. Cinacalcet is the first allosteric GPCR modulator to enter the market, which demonstrates that the therapeutic principle of allosteric modulation can also be extended to this important drug target class. In this review we outline the structure and function of family C GPCRs with particular focus on the ligand binding sites, and we present the most important pharmacological agents and the therapeutic prospects of the receptors.

Papel de los FAE en el tratamiento del dolor neuropático. Mecanismos de acción de la gabapentina / No disponible

El dolor neuropático se define como: 'dolor irradiado o causado por una lesión primaria o disfunción del sistema nervioso central o periférico'. Es por lo tanto consecuencia directa de una lesión o de una enfermedad que afecta al sistema nervioso, tanto la hiperexcitabilidad neuronal como los cambios moleculares que ocurren en el dolor neuropático van a presentar características comunes con los cambios celulares de algunos tipos de epilepsia. Debido a ello, desde hace mucho tiempo se han administrado fármacos antiepilépticos en el tratamiento de este tipo de dolor, si bien de algunos de ellos todavía no están claros cuáles son los mecanismos que le permiten actuar sobre el dolor. En este grupo podríamos encuadrar a la gabapentina, que es un FAE de segunda generación con la indicación de utilización en los casos de dolor neuropático. La gabapentina es un derivado del ácido gammaaminobutírico (GABA) que está comercializado en España desde el año 1995. Todavía no se conocen cuáles son sus mecanismos de actividad analgésica si bien, la posibilidad más explorada es la que la relaciona con la subunidad alfa-2- delta de los canales de calcio voltaje dependientes. A través de la modulación de los canales de calcio la gabapentina interrumpiría determinados procesos que cursan con hiperexcitabilidad neuronal al inhibir directamente la liberación de glutamato. Posiblemente, estos mecanismos de acción a través de los cuales ejerce la gabapentina su acción analgésica se puedan confirmar en un corto periodo de tiempo (AU)

Neuroathic pain is defined as: 'pain irradiating from or caused by a primary injury or dysfunction of the central or peripheral nervous system'. Thus, it is the direct consequence of an injury or disease involving the nervous system and both the neuronal hyperexcitability and the molecular changes that occurs in the neuropathic pain are going to present common features with the cellular changes of some types of epilepsy. On account of this, antiepileptic drugs have been administered for a long time in the management of this type of pain, although the mechanisms through which some of them act on pain are still unclear. Gabapentine, a second generation AED recommended for neuropathic pain, would be placed within this group. Gabapentine is a derivative of the gamma-aminobutyric acid (GABA) that was launched in the Spanish market in 1995. Its mechanisms of analgesic activity are still unknown, but the most explored option relates it with the alpha-2-delta sub-unit of voltage-dependant calcium channels. Through the modulation of calcium channels, gabapentine would discontinue some processes that cause neuronal hyperexcitability by directly inhibiting the release of glutamate. These mechanisms of action through which gabapentine provides analgesia will probably be confirmed in the short -term (AU)