Molecular and Cellular Mechanisms of Sporadic Alzheimer's Disease: Studies on Rodent Models in vivo.

In this review, recent data are presented on molecular and cellular mechanisms of pathogenesis of the most widespread (about 95%) sporadic forms of Alzheimer's disease obtained on in vivo rodent models. Although none of the available models can fully reproduce the human disease, several key molecular mechanisms (such as dysfunction of neurotransmitter systems, especially of the acetylcholinergic system, ß-amyloid toxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction, disturbances in neurotrophic systems) are confirmed with different models. Injection models, olfactory bulbectomy, and senescence accelerated OXYS rats are reviewed in detail. These three approaches to in vivo modeling of sporadic Alzheimer's disease have demonstrated a considerable similarity in molecular and cellular mechanisms of pathology development. Studies on these models provide complementary data, and each model possesses its specific advantages. A general analysis of the data reported for the three models provides a multifaceted and the currently most complete molecular picture of sporadic Alzheimer's disease. This is highly relevant also from the practical viewpoint because it creates a basis for elaboration and preclinical studies of means for treatment of this disease.

Actions of pulsed ultra-broadband electromagnetic irradiation on the EEG and sleep in laboratory animals.

Irradiation of animals with ultrashort impulses of ultra-broadband magnetic irradiation with an impulse repetition frequency of 6 Hz for 1 h induced changes in the spectral composition of cerebral cortex electrical activity in rats, measured over the 5 min immediately after irradiation, as compared with controls. In particular, there was suppression of frequencies close to the impulse sequence frequency, along with a decrease in interhemisphere coherence. Continuous recording of polygrams for 22 h from rabbits after irradiation revealed a "delayed" effect--a significant increase in paradoxical sleep, starting 16 h after the end of irradiation and persisting to the end of the recording period. It is suggested that irradiation has a direct action both on the mechanisms of generation of the theta rhythm (septohippocampal) and on the system controlling circadian rhythms (the suprachiasmatic nucleus-epiphysis system).

Analysis of cyclic adenosine-3',5'-monophosphate levels in structures of the "informational" and "motivational" systems of the rat brain during acquisition of a conditioned active avoidance reaction.

Cyclic adenosine-3'5'-monophosphate (cAMP) levels in structures of the "informational" and "motivational" systems of the brain were measured during acquisition of a conditioned two-sided active avoidance reflex in rats. cAMP levels were measured in three groups of animals--intact animals, trained animals, and an active control group (given uncombined presentations of the conditioned (light) and unconditioned (electric shock) stimuli)--immediately after reproduction of the acquired reflex. Significant accumulation of cAMP levels in brain structures was seen in animals of the active control group in the hypothalamus and in trained animals in the left and right hippocampus and the right frontal cortex. Positive correlations were found between cAMP levels in symmetrical parts of the frontal cortex, amygdala, and hypothalamus in animals of all study groups. In addition, active control rats and trained rats showed interhemisphere and intrahemisphere correlations between cAMP levels in brain macrostructure, whose patterns were specific for each group. The pattern of correlations observed here is assessed from the point of view of the role of the "informational" and "motivational" structures in the organization of adaptive behavior.

Role of nitric oxide in the ethylcholine aziridinium model of delayed apoptotic neurodegeneration in vivo and in vitro.

The involvement of nitric oxide in neurodegenerative processes still remains incompletely characterized. Although nitric oxide has been reported to be an important mediator in neuronal degeneration in different models of cell death involving NMDA-receptor activation, increasing evidence for protective mechanisms has been obtained. In this study the role of nitric oxide was investigated in a model of NMDA-independent, delayed apoptotic cell death, induced by the neurotoxin ethylcholine aziridinium ethylcholine aziridinium both in vivo and in vitro. For the in vivo evaluation rats received bilateral intracerebroventricular injections of ethylcholine aziridinium (2nmol/ventricle) or vehicle. In the hippocampus a transient decrease in nitric oxide synthase activity occurred, reaching its lowest levels three days after ethylcholine aziridinium treatment (51.7+/-9.8% of controls). The decrease coincided with the maximal reduction in choline acetyltransferase activity as marker for the extent of cholinergic lesion. The effect of pharmacological inhibition of nitric oxide synthase was tested by application of various nitric oxide synthase inhibitors with different selectivity for the nitric oxide synthase-isoforms. Unspecific nitric oxide synthase inhibition resulted in a significant potentiation of the loss of choline acetyltransferase activity in the hippocampus measured seven days after ethylcholine aziridinium application, whereas the specific inhibition of neuronal or inducible nitric oxide synthase was ineffective. These pharmacological data are suggestive for a neuroprotective role of nitric oxide generated by endothelial nitric oxide synthase. In vitro experiments were performed using serum-free primary neuronal cell cultures from hippocampus, cortex and septum of E15-17 Wistar rat embryos. Ethylcholine aziridinium-application in a range of 5-80microM resulted in delayed apoptotic neurodegeneration with a maximum after three days as confirmed by morphological criteria, life-death assays and DNA laddering. Nitric oxide synthase activity in harvested cells decreased in a dose- and time-dependent manner. Nitric oxide production as determined by measurement of the accumulated metabolite nitrite in the medium was equally low in controls and in ethylcholine aziridinium treated cells (range 0.77-1.86microM nitrite). An expression of inducible nitric oxide synthase messenger RNA could not be detected by semiquantitative RT-PCR 13h after ethylcholine aziridinium application. The present data indicate that in a model of delayed apoptotic neurodegeneration as induced by ethylcholine aziridinium neuronal cell death in vitro and in vivo is independent of the cytotoxic potential of nitric oxide. This is confirmed by a decrease in nitric oxide synthase activity, absence of nitric oxide production and absence of inducible nitric oxide synthase expression. In contrast, evidence for a neuroprotective role of nitric oxide was obtained in vivo as indicated by the exaggeration of the cholinergic lesion after unspecific nitric oxide synthase inhibition by N-nitro-L-arginine methylester.