RESUMO
Severe loss of cholinergic neurons in the basal forebrain nuclei and of noradrenergic neurons in the locus coeruleus are almost invariant histopathological hallmarks of Alzheimer's disease. However, the role of these transmitter systems in the spectrum of cognitive dysfunctions typical of the disease is still unclear, nor is it yet fully known whether do these systems interact and how. Selective ablation of either neuronal population, or both of them combined, were produced in developing animals to investigate their respective and/or concurrent contribution to spatial learning and memory, known to be severely affected in Alzheimer's disease. Single or double lesions were created in 4-8 days old rats by bilateral intraventricular infusion of two selective immunotoxins. At about 16 weeks of age, the animals underwent behavioural tests specifically designed to evaluate reference and working memory abilities, and their brains were later processed for quantitative morphological analyses. Animals with lesion to either system alone showed no significant reference memory deficits which, by contrast, were evident in the double-lesioned subjects. These animals could not adopt an efficient search strategy on a given testing day and were unable to transfer all relevant information to the next day, suggesting deficits in acquisition, storage and/or recall. Only animals with single noradrenergic or double lesions exhibited impaired working memory. Interestingly, ablation of cholinergic afferents to the hippocampus stimulated a robust ingrowth of thick fibres from the superior cervical ganglion which, however, did not appear to have contributed to the observed cognitive performance. Ascending cholinergic and noradrenergic afferents to the hippocampus and neocortex appear to be primarily involved in the regulation of different cognitive domains, but they may functionally interact, mainly at hippocampal level, for sustaining normal learning and memory. Moreover, these transmitter systems are likely to compensate for each other, but apparently not via ingrowing sympathetic fibres.
RESUMO
Plastic changes have been reported in the SOD1-G93A mouse model of amyotrophic lateral sclerosis, a disorder characterized by progressive motoneuronal loss; however, whether these changes related with the onset and development of motor impairments is still unclear. Here, the functional and anatomical changes taking place in SOD1-G93A mice and their time course were investigated during ongoing motoneuronal degeneration. Starting from about 4 postnatal weeks, SOD1-G93A and wild-type (WT) mice were evaluated in the rotarod test, to be sacrificed at about 12-13 or 19 weeks of age, and their lumbar spinal cords were processed for histo- and immunohistochemistry. Compared to age-matched WT controls, 12 weeks-old SOD1-G93A mice exhibited relatively mild or no motor impairments in the rotarod test, in spite of a dramatic (≈60%, as estimated by stereology) loss of choline acetyl-transferase (ChAT)-immunoreactive motoneurons which remained virtually unchanged in SOD1-G93A mice surviving up to 19 weeks. Notably, the functional sparing in SOD1-G93A mice at 12 weeks was paralleled by a marked ≈50% increase in motoneuron volume and a near-normal density of acetylcholinesterase-positive process arborization, which was significantly increased when analyzed as ratio to the decreased number of ChAT-positive motoneurons. By contrast, at 19 weeks, when motor deficits had become dramatically evident, both measures were found reverted to about 50-60% of control values. Thus, at specific stages during the progression of the disease, robust compensatory events take place in surviving motoneurons of SOD1-G93A mice, which sustain motor performance, and whose full understanding may highlight a valuable therapeutic opportunity window.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Neurônios Motores/patologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Medula Espinal/patologia , Medula Espinal/fisiopatologiaRESUMO
Noradrenergic neurons in the locus coeruleus play a role in learning and memory, and their loss is an early event in Alzheimer's disease pathogenesis. Moreover, noradrenaline may sustain hippocampal neurogenesis; however, whether are these events related is still unknown. Four to five weeks following the selective immunotoxic ablation of locus coeruleus neurons, young adult rats underwent reference and working memory tests, followed by postmortem quantitative morphological analyses to assess the extent of the lesion, as well as the effects on proliferation and/or survival of neural progenitors in the hippocampus. When tested in the Water Maze task, lesioned animals exhibited no reference memory deficit, whereas working memory abilities were seen significantly impaired, as compared with intact or sham-lesioned controls. Stereological analyses confirmed a dramatic noradrenergic neuron loss associated to reduced proliferation, but not survival or differentiation, of 5-bromo-2'deoxyuridine-positive progenitors in the dentate gyrus. Thus, ascending noradrenergic afferents may be involved in more complex aspects of cognitive performance (i.e., working memory) possibly via newly generated progenitors in the hippocampus.
Assuntos
Neurônios Adrenérgicos/patologia , Neurônios Adrenérgicos/fisiologia , Hipocampo/fisiologia , Transtornos da Memória/etiologia , Memória/fisiologia , Neurogênese , Norepinefrina/deficiência , Norepinefrina/fisiologia , Doença de Alzheimer/etiologia , Animais , Proliferação de Células , Feminino , Hipocampo/citologia , Hipocampo/patologia , Ratos Sprague-DawleyRESUMO
Sigma-1 receptor agonists have recently attracted much attention as potential therapeutic drugs for cognitive and affective disorders, however, it is still unclear whether they act via modulation of transmitter release or activation of sigma-1 receptors in memory-related brain regions. In the present study,we have investigated the anti-amnesic and neuroprotective actions of the compound (-)-methyl (1S,2R)-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane-carboxylate) [(-)-MR22],a selective sigma-1 receptor agonist able to protect cultured cortical neurons from amyloid toxicity. To this aim, cognitive deficits, cholinergic loss, and amyloid peptide accumulation were obtained in the rat by simultaneous injections of a selective immunotoxin and pre-aggregated amyloid peptide into the basal forebrain and the hippocampus, respectively. At about fivesix weeks post-lesion, the double-lesioned animals exhibited dramatic deficits in spatial learning and memory, whereas animals with single injections of either compound were not or only marginally affected, in spite of equally severe cholinergic loss oramyloid deposition. Administration of (-)-MR22 appeared to reverse cognitive impairments in double lesioned animals, whereas pre-treatment with the selective sigma-1 antagonist BD1047 abolished this effect. Moreover, (-)-MR22 normalized the levels of cell-associated amyloid-ß protein precursor (AßPP) in the neocortex and hippocampus, thus sustaining a non-amyloidogenic AßPP processing. By contrast, treatment with (-)-MR22 produced no effects whatsoever in intact animals. Thus, sigma-1 receptor agonists such as (-)-MR22 may ameliorate perturbed cognitive abilities and exert a protective action onto target neurons, holding promises as viable tools for memory enhancement and neuroprotection.
Assuntos
Amiloide/toxicidade , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/tratamento farmacológico , Colinérgicos/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Receptores sigma/agonistas , Acetilcolinesterase , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Análise de Variância , Animais , Anticorpos Monoclonais/toxicidade , Lesões Encefálicas/complicações , Ciclopropanos/uso terapêutico , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/etiologia , Atividade Motora/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saporinas , Fatores de Tempo , Receptor Sigma-1RESUMO
The possibility to selectively remove noradrenergic neurons in the locus coeruleus/subcoeruleus (LC/SubC) complex by the immunotoxin anti-dopamine-beta-hydroxylase (DBH)-saporin has offered a powerful tool to study the functional role of this projection system. In the present study, the anatomical consequences of selective lesions of the LC/SubC on descending noradrenergic projections during early postnatal development have been investigated following bilateral intraventricular injections of anti-DBH-saporin or 6-hydroxydopamine to immature (4 day old) rats. Administration of increasing doses (0.25-1.0 microg) of the immunotoxin produced, about 5 weeks later, a dose-dependent loss of DBH-immunoreactive neurons in the LC/SubC complex (approximately 45-90%) paralleled by a similar reduction of noradrenergic innervation in the terminal territories in the lumbar spinal cord. Even at the highest dose used (1.0 microg) the immunotoxin did not produce any detectable effects on dopaminergic, adrenergic, serotonergic or cholinergic neuronal populations, which, by contrast, were markedly reduced after administration of 6-hydroxydopamine. The approximately 90% noradrenergic depletion induced by 0.5 and 1.0 microg of anti-DBH-saporin remained virtually unchanged at 40 weeks post-lesion. Conversely, the approximately 45% reduction of spinal innervation density estimated at 5 weeks in animals injected with the lowest dose (0.25 microg) of the immunotoxin was seen recovered up to near-normal levels at 40 weeks, possibly as a result of the intrinsic plasticity of the developing noradrenergic system. A similar reinnervation in the lumbar spinal cord was also seen promoted by grafts of fetal LC tissue implanted at the postnatal day 8 (i.e. 4 days after the lesion with 0.5 microg of anti-DBH-saporin). In these animals, the number of surviving neurons in the grafts and the magnitude of the reinnervation, with fibers extending in both the grey and white matter for considerable distances, were seen higher than those reported in previous studies using adult recipients. This would suggest that the functional interactions between the grafted tissue and the host may recapitulate the events normally occurring during the ontogenesis of the coeruleo-spinal projection system, and can therefore be developmentally regulated. Thus, the neonatal anti-DBH-saporin lesion model, with the possibility to produce graded noradrenergic depletions, holds promises as a most valuable tool to address issues of compensatory reinnervation and functional recovery in the severed CNS as well as to elucidate the mechanisms governing long-distance axon growth from transplanted neural precursors.
Assuntos
Transplante de Tecido Encefálico/métodos , Locus Cerúleo/crescimento & desenvolvimento , Neurônios/patologia , Norepinefrina/fisiologia , Animais , Denervação/efeitos adversos , Denervação/métodos , Modelos Animais de Doenças , Feminino , Sobrevivência de Enxerto/fisiologia , Locus Cerúleo/citologia , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Neurotoxinas/toxicidade , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saporinas , Fatores de TempoRESUMO
Previous studies have reported that selective sigma-1 agonists may improve cognitive abilities in experimental animals possibly via a cholinergic mechanism. However, the issue of a direct action on to sigma-1 receptors in memory-related brain areas has been much less investigated. The newly synthetised compound methyl(1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(+/-)-PPCC] has recently been shown to possess high affinity for the sigma-1 receptor where it specifically acts as an agonist. Here, the functional effects of (+/-)-PPCC were investigated in rat models of mild or severe cognitive dysfunction based on a sub-total (