RESUMEN
The neuropathology of Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra. We have recently shown that the activation of protein kinase A improves the survival of dopaminergic neurons in culture and, furthermore, protects them from the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+) in vitro. We have now analysed the potential of phosphodiesterase inhibitors to increase cAMP levels in dopaminergic neurons, to improve their survival in culture and to protect them from the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo. Increasing intracellular cAMP with phosphodiesterase type IV-specific inhibitors enhanced the survival of dopaminergic neurons in culture. Inhibitors of other phosphodiesterase types were not active. In vivo, phosphodiesterase type IV inhibitors reduced the MPTP-induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra of these animals was diminished. After Nissl staining, a similar reduction of the MPTP-induced loss of neurons was observed in the substantia nigra. The protective effect of protein kinase A activation did not appear to be due to the blocking of MPP+ uptake into dopaminergic neurons. This was not decreased after treatment with forskolin or 8-(4-chlorophenylthio)-cAMP. Thus, protein kinase A regulates the survival and differentiation of dopaminergic substantia nigra neurons in vivo, implicating a therapeutic potential for substances which regulate cAMP turnover in these neurons.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Dopamina/metabolismo , Intoxicación por MPTP , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Hidrolasas Diéster Fosfóricas/farmacología , Sustancia Negra/efectos de los fármacos , Animales , Células Cultivadas/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , RatasRESUMEN
The indolonaphthyridine 8 is described as a selective 5-HT2C/2B vs 5-HT2A receptor antagonist. The compound was synthesized in seven steps starting from indoline and isonicotinic acid chloride. The key step is a photocyclization of the indolinyl tetrahydropyridinocarbamic acid ethyl ester 4 to the cis-octahydroindolo[1, 7-bc][2,6]naphthyridinecarbamic acid ethyl ester 5. The synthesis was accomplished by reduction with aluminum hydride and racemic resolution. The indolonaphthyridine 8 exerted the binding profile of a selective 5-HT2C receptor ligand (pKD 7.8) and behaved as an antagonist on the 5-HT-induced accumulation of inositol phosphates in pig choroid plexus cells (pKB 7.13). Compound 8 dose-dependently inhibited the ACTH response to MK-212 in rats and the MK-212-induced hypophagic effect with an ID50 value of 0.3 mg/kg sc. Compound 8 acted as a 5-HT2B receptor antagonist at the rat stomach fundus with a pKB value of 7.34.
Asunto(s)
Naftiridinas/síntesis química , Naftiridinas/farmacología , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Cinética , Masculino , Ratas , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Antagonistas de la Serotonina/metabolismoRESUMEN
Investigations with four dihydrogenated ergot alkaloids, dihydroergotoxine, dihydroergonine, dihydroergostine and dihydro-beta-ergosine indicate that they exert similar dose dependent effects on the sleep-wakefulness cycle of the rat. The duration of wakefulness was increased, non-rapid eye movement (NREM) and, in particular, rapid eye movement (REM) sleep were shortened. 5-Hydroxytryptophan, but not apomorphine, induced similar changes of the rat sleep-wakefulness cycle. Neurochemical studies on rat brain biogenic amines indicate that dihydroergotoxine lowers homovanillic acid (HVA) levels and reduces HVA elevations after morphine or haloperidol in the striatum. In addition, the turnover of serotonin was slowed down and 5-hydroxyindoleacetic acid (5-HIAA) content in the whole brain was reduced. 5-HIAA elevation induced by clozapine was inhibited. These results suggest that the electroencephalographic changes in the rat produced by treatment with dihydrogenated ergot alkaloids reflect an enhanced level of vigilance and could be related to changes of brain biogenic amine metabolism.