RESUMO
The organophosphate cholinesterase (ChE) inhibitor paraoxon is the oxidized active metabolite of parathion, a pesticide whose use in agriculture has been matter of increasing concern. The present work was aimed at reproducing a prolonged exposure to low concentrations of paraoxon and assessing possible damage to the hippocampus during the period of most significant cholinergic development. Male Wistar rats were given, from P8 to P20, subcutaneous daily injections of paraoxon (0.1, 0.15 and 0.2mg/kg). The rate of body weight gain was reduced by all doses of paraoxon and brain ChE activity progressively decreased up to 60% by P21. Some deaths occurred in the beginning of the treatment, but the surviving animals showed neither convulsions nor overt signs of cholinergic hyperstimulation. Morphometric analysis of Lucifer Yellow-stained CA1 pyramidal neurons in coronal sections of the hippocampus showed that by P21 paraoxon caused a decrease in spine density on basal but not on secondary apical dendrites. The dendritic arborization and the pyramidal and granular cell body layers were not altered by paraoxon. ChE staining decreased in all hippocampal and dentate gyrus regions studied, whereas choline acetyltransferase (ChAT) and zinc-positive fibers remained as in control. In summary, chronic exposure to low paraoxon concentrations during the period of rapid brain development caused significant and selective decrease in basal dendritic spine density of the CA1 pyramidal neurons. Distinct modulation of the basal tree at the stratum oriens by the interplay of cholinergic afferent and GABAergic interneurons, as well as the remodeling process in response to a repetitive and rather mild paraoxon insult, may account for this selective susceptibility of basal dendritic spines. The hippocampal alterations described here occurred in the absence of toxic cholinergic signs and may affect brain development and cause functional deficits that could continue into adulthood.
Assuntos
Dendritos/efeitos dos fármacos , Inseticidas/administração & dosagem , Paraoxon/administração & dosagem , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Animais Recém-Nascidos , Contagem de Células/métodos , Dendritos/fisiologia , Relação Dose-Resposta a Droga , Exposição Ambiental/efeitos adversos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Masculino , Células Piramidais/enzimologia , Ratos , Ratos WistarRESUMO
A new family of tacrine (THA) analogues (7-9, 12), containing the azaheterocyclic pyrazolo[4,3-d]pyridine or pyrazolo[3,4-b][1,8]naphthyridine systems as isosteres of the quinoline ring of THA, has been synthesized. The compounds were tested in rat brain cholinesterases using Ellman's method, and all were fully efficacious in inhibiting the enzymes. Compounds 9 and 12b were the most potent against acetylcholinesterase (AChE), showing IC(50) of 6.0 and 6.4 microM, and were less active against rat brain butyrylcholinesterase, showing selectivity indexes of 5.3 and 20.9, respectively. Compounds 7-9 and 12 were also tested for their acute neurotoxicity in vitro, using cultured rat cortical cells. Compounds 7 and 8 were not significantly toxic; 9 was toxic at 500 microM, but not at 100 microM. The naphthyridine derivatives 12a and 12b showed a significant concentration-dependent neurotoxicity, being able to kill most cells at 500 microM. Molecular dynamic simulation using the X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new THA isosteres.
Assuntos
Inibidores da Colinesterase/síntese química , Naftiridinas/síntese química , Fármacos Neuroprotetores/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Acetilcolinesterase/química , Animais , Butirilcolinesterase/química , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Cristalografia por Raios X , Modelos Moleculares , Naftiridinas/química , Naftiridinas/toxicidade , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/toxicidade , Pirazóis/química , Pirazóis/toxicidade , Piridinas/química , Piridinas/toxicidade , Ratos , Ratos Wistar , Relação Estrutura-Atividade , TorpedoRESUMO
Nitric oxide (NO) is synthesized in cells of both the central and peripheral nervous system and has been implicated in several forms of synaptic plasticity. The enzyme that produces NO, nitric oxide synthase (NOS), can be visualized in the brain by the reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemistry technique (NADPH-d). We have used NADPH-d activity to detect the presence of NOS-positive cells in the developing rat superior colliculus. Our results showed that NOS is present in cells and neuropil in the developing and adult rat superior colliculus. The first NOS-positive cells appeared at postnatal day 7 and were weakly stained. The number and intensity of the NOS-positive cells increased progressively during the following days reaching a maximum at postnatal day 15. By the end of the third postnatal week, both the number and intensity of stained cells showed an adult-like pattern. The NOS-positive cells showed a Golgi-like mosphology and we have found that all cell types present in the superior colliculus express the enzyme. The expression of NOS by tectal cells parallels the functional development of the retino-collicular and cortico-tectal projections and suggest that nitric oxide synthase-positive cells might be involved in this process. In this review we highlighted some of the recent descriptions of the expression of NOS in the mammalian visual system with emphasis in the superior colliculus and correlate these findings with several developmental events taking place in this structure.