RESUMO
A degradation of the nigrostriatal dopaminergic (DA-ergic) system is the key component of pathogenesis of Parkinson's disease (PD). Initial clinical symptoms appear 20-30 years after the onset of neurodegeneration, at a 70% DA depletion in the striatum and a 50% loss of nigral DA-ergic neurons. Low efficacy of the therapy might be improved if preclinical diagnostics and preventive therapy are developed. The development of appropriate experimental models should precede clinical trials. This multidisciplinary study first managed to model in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) all together the following stages of parkinsonism: (a) the early presymptomatic stage manifested by a subthreshold degeneration of axons and DA depletion in the striatum without loss of nigral cell bodies; (b) the advanced presymptomatic stage manifested by a subthreshold degeneration of striatal axons and DA depletion and by a subthreshold loss of nigral cell bodies; (c) the advanced presymptomatic stage characterized by threshold depletion of striatal DA and a loss of DA-ergic axons and nigral cell bodies resulting in motor dysfunction. The degeneration of axons proceeds and prevails that of cell bodies suggesting higher sensitivity to MPTP of the former. Compensatory processes were developed in parallel to neurodegeneration that was manifested by the increase of the DA content in individual nigral cell bodies and DA turnover in the striatum. The developed models might be exploited for: (a) an examination of pathogenetic mechanisms not only in the nigrostriatal system but also in other brain regions and in the periphery; (b) a study of the compensatory mechanisms under DA deficiency; (c) a search of precursors of motor disorders and peripheral biomarkers in presymptomatic parkinsonism; (d) the development of preventive therapy aiming to slow down the neurodegeneration and strengthen compensatory processes. Thus, the models of the early and advanced presymptomaic stages and of the early symptomatic stage of parkinsonism were developed in mice with MPTP.
Assuntos
Corpo Estriado/fisiopatologia , Dopamina/deficiência , Degeneração Neural/fisiopatologia , Vias Neurais/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Substância Negra/fisiopatologia , Animais , Corpo Estriado/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Vias Neurais/patologia , Substância Negra/patologiaRESUMO
Changes in the phospholipid composition of cardiomyocyte plasma membranes during hemorrhagic shock suggest that disturbances in phosphatidylethanolamine metabolism serve as one of the major factors for myocardial alteration in shock. Depletion of membrane phosphatidylcholine causes destruction of cardiomyocytes. The enhanced breakdown of membrane sphingomyelin at the late stage of hemorrhagic shock is considered as a mechanism, which induces apoptosis in cardiomyocytes and Ca(2+) accumulation in these cells. A simultaneous increase in the content of membrane phosphatidylserine is the mechanism of activation of opioid receptors, which plays a compensatory role.
Assuntos
Membrana Celular/metabolismo , Miócitos Cardíacos/metabolismo , Fosfolipídeos/metabolismo , Choque Hemorrágico/metabolismo , Animais , Apoptose , Cálcio/análise , Gatos , Miócitos Cardíacos/ultraestrutura , Fosfatidilcolinas/análise , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfatidilserinas/análise , Fosfatidilserinas/metabolismo , Receptores Opioides/metabolismo , Esfingomielinas/metabolismoRESUMO
Degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system is the key stage in the pathogenesis of Parkinson's disease. The first symptoms of this disease are observed after degeneration of 70-80% neurons, which occurs over 20-30 years. The clinical stage of Parkinson's disease begins after this period. Late diagnostics of Parkinson's disease contributes to low efficiency of therapy for this disorder. Detailed study of the pathogenesis and development of preclinical diagnostic methods for Parkinson's disease are the urgent problems. This work was designed to develop a new experimental model of the preclinical and clinical stages of the disease. Experimental modeling was performed on C57Bl/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This agent is converted into the MPP(+)-neurotoxin in brain DAergic neurons. We showed that MPTP in a dose of 4 mg/kg has no effect on the nigrostriatal DAergic system. MPTP in a dose of 8-16 mg/kg produced the toxic effect only on DAergic axons, which simulates the preclinical stage of Parkinson's disease. MPTP in a dose of 20-40 mg/kg had the toxic effect on neuronal axons and bodies, which simulates the clinical stage of Parkinson's disease. The data suggest that progressive degeneration of DAergic neurons is accompanied by activation of compensatory mechanisms for functional deficiency of these cells.
Assuntos
Neurônios Dopaminérgicos/patologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/patologia , Serotonina/análise , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologiaRESUMO
Combined pain and depression status in rats was created by inducing experimental depressive syndrome (by subchronic injection of MPTP proneurotoxin) in animals with manifest and developing neurogenic pain syndrome induced by preliminary crossing of the sciatic nerve in the hind limb. The neurogenic pain syndrome augmented by some parameters the depressive symptoms and provoked manifestation of signs of depressive behavior in animals treated with saline.
Assuntos
Depressão/induzido quimicamente , Dor , Neuropatia Ciática/complicações , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Ansiedade/etiologia , Axotomia , Comportamento Animal/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Masculino , Modelos Animais , Atividade Motora/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The active loading of liposomes with dopamine in response to an ammonium sulfate gradient was studied. This method can be regarded as a mean to more efficiently improve the liposomal dopamine/lipids ratio in comparison to conventional methods of liposome preparation. Trapping efficiency of dopamine into liposomes exhibiting a transmembrane ammonium sulfate gradient was shown to be dependent on liposome lipid composition, lipid concentration and temperature. Dopamine-containing liposomes with alpha-tocopherol in the lipid bilayer were shown to be stable at least for three weeks. It has been found that intraperitoneal (i.p.) administration of conventionally prepared dopamine-containing liposomes as well as liposomes with increased dopamine/lipid ratio may efficiently suppress the expression of parkinsonian symptoms in C57BL/6 mice with experimental parkinsonian syndrome. On the other hand, only through increasing of liposomal dopamine/lipid ratio the complete compensation of dopamine deficiency in the mice brain was achieved. The obtained data may be considered as biochemical evidence in favor of liposomes' ability to act as a carrier system for the delivery of dopamine into the brain.
RESUMO
Intraventricular injection of cerebrospinal fluid (CSF) obtained from cats with chronic electrical stimulation of cerebellar vermal cortex resulted in suppression of epileptic foci activity in cat brain cortex, an increase in time to first seizure, and weakening of generalized seizures in rats. The CSF obtained from cats after electroshock seizures induced less pronounced, although significant antiepileptic action in comparison with the CSF of cats with cerebellar stimulation on the model of generalized seizures in rats. The antiepileptic action of CSF obtained from cats with electrostimulation of cerebellar vermis and from electroshock cats is due to appearance of peptide factors in CSF.
Assuntos
Anticonvulsivantes , Cerebelo/fisiologia , Líquido Cefalorraquidiano/fisiologia , Epilepsia/prevenção & controle , Animais , Gatos , Líquido Cefalorraquidiano/análise , Estimulação Elétrica , Eletrochoque , Epilepsia/etiologia , Feminino , Injeções Intraventriculares , Masculino , Pentilenotetrazol/efeitos adversos , Peptídeos/análise , Peptídeos/farmacologia , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
The stereotyped behavior syndrome was induced in rats through local impairment of inhibitory GABA-ergic mechanisms in both caudate nuclei by bilateral microinjection of tetanus toxin, penicillin, or picrotoxin into the rostral part of the caudate nucleus. Intraperitoneally injected haloperidol suppressed the syndrome; this effect was dose-dependent. The same effect on the tetanus toxin-induced stereotyped behavior was produced by GABA microinjected bilaterally into the rostral part of the caudate nucleus of unrestrained rats. It was found in this model of tetanus toxin-induced stereotyped behavior that lithium chloride and diazepam can suppress the syndrome. Combined application of lithium chloride, diazepam, and haloperidol in minimal effective doses resulted in a much more complete and longer-lasting suppression of the syndrome than the separate use of these drugs. This effect is attributed to the joint specific actions of the drugs on pathogenetically interrelated components of a hyperactive determinant structure that arises in the caudate nuclei after impairment of the GABA control and this is responsible for the stereotyped behavior syndrome.