RESUMO
Inhibitory GABAergic and glycinergic neurotransmission in the spinal cord play a central role in the regulation of neuronal excitability, by maintaining a balance with the glutamate-mediated excitatory transmission. Glutamatergic agonists infusion in the spinal cord induce motor neuron death by excitotoxicity, leading to motor deficits and paralysis, but little is known on the effect of the blockade of inhibitory transmission. In this work we studied the effects of GABAergic and glycinergic blockade, by means of microdialysis perfusion (acute administration) and osmotic minipumps infusion (chronic administration) of GABA and glycine receptors antagonists directly in the lumbar spinal cord. We show that acute glycinergic blockade with strychnine or GABAergic blockade with bicuculline had no significant effects on motor activity and on motor neuron survival. However, chronic bicuculline infusion, but not strychnine, induced ipsilateral gait alterations, phalange flaccidity and significant motor neuron loss, and these effects were prevented by AMPA receptor blockade with CNQX but not by NMDA receptor blockade with MK801. In addition, we demonstrate that the chronic infusion of bicuculline enhanced the excitotoxic effect of AMPA, causing faster bilateral paralysis and increasing motor neuron loss. These findings indicate a relevant role of GABAergic inhibitory circuits in the regulation of motor neuron excitability and suggest that their alterations may be involved in the neurodegeneration processes characteristic of motor neuron diseases such as amyotrophic lateral sclerosis.
Assuntos
Bicuculina/toxicidade , Antagonistas GABAérgicos/toxicidade , Atividade Motora/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Medula Espinal/efeitos dos fármacos , Estricnina/toxicidade , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Atrofia/induzido quimicamente , Bicuculina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Interações Medicamentosas , Marcha/efeitos dos fármacos , Masculino , Hipotonia Muscular/induzido quimicamente , Ratos , Receptores de Glicina/antagonistas & inibidores , Estricnina/antagonistas & inibidores , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidadeRESUMO
Neural mechanisms underlying the onset and maintenance of epileptic seizures involve alterations in inhibitory and/or excitatory neurotransmitter pathways. Thus, the prospecting of novel molecules from natural products that target both inhibition and excitation systems has deserved interest in the rational design of new anticonvulsants. We isolated the alkaloids (+)-erythravine and (+)-11-α-hydroxy-erythravine from the flowers of Erythrina mulungu and evaluated the action of these compounds against chemically induced seizures in rats. Our results showed that the administration of different doses of (+)-erythravine inhibited seizures evoked by bicuculline, pentylenetetrazole, and kainic acid at maximum of 80, 100, and 100%, respectively, whereas different doses of (+)-11-α-hydroxy-erythravine inhibited seizures at a maximum of 100% when induced by bicuculline, NMDA, and kainic acid, and, to a lesser extent, PTZ (60%). The analysis of mean latency to seizure onset of nonprotected animals, for specific doses of alkaloids, showed that (+)-erythravine increased latencies to seizures induced by bicuculline. Although (+)-erythravine exhibited very weak anticonvulsant action against seizures induced by NMDA, this alkaloid increased the latency in this assay. The increase in latency to onset of seizures promoted by (+)-11-α-hydroxy-erythravine reached a maximum of threefold in the bicuculline test. All animals were protected against death when treated with different doses of (+)-11-α-hydroxy-erythravine in the tests using the four chemical convulsants. Identical results were obtained when using (+)-erythravine in the tests of bicuculline, NMDA, and PTZ, and, to a lesser extent, kainic acid. Therefore, these data validate the anticonvulsant properties of the tested alkaloids, which is of relevance in consideration of the ethnopharmacological/biotechnological potential of E. mulungu.
Assuntos
Anticonvulsivantes/uso terapêutico , Fabaceae , Flores/química , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Fitoterapia/métodos , Extratos Vegetais/uso terapêutico , Convulsões/tratamento farmacológico , Animais , Bicuculina/toxicidade , Distribuição de Qui-Quadrado , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fabaceae/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Injeções Intraventriculares , Ácido Caínico/toxicidade , Masculino , N-Metilaspartato/toxicidade , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Convulsões/induzido quimicamenteRESUMO
Wet dog shakes (WDS) and head shakes (HS) are associated with experimentally induced convulsive seizures. We sought to determine whether these behaviors are correlated or not with major (status epilepticus (SE) or fully kindled animals) or minor (non-SE or partially kindled animals) seizure severity. WDS are directly correlated with SE induced by intracerebral star fruit extract (Averrhoa carambola) injection and with kindled animals in the amygdala fast kindling model. On the other hand, WDS are inversely correlated with SE induced by intracerebral bicuculline and pilocarpine injections. Systemic pilocarpine in animals pretreated with methyl-scopolamine barely induced WDS or HS. The role of shaking behaviors may vary from ictal to anticonvulsant depending on the experimental seizure model, circuitries involved, and stimulus intensity. The physical presence of acrylic helmets may per se inhibit the HS response. Also, methyl-scopolamine, a drug incapable of crossing the blood-brain barrier, can induce HS in animals without acrylic helmets.