RESUMEN
Physiological enzymatic cleavage of membrane phospholipids by phospholipase A2 (PLA2) results in normal levels of phosphomonoester and phosphodiester, by which a normal dopamine neurotransmission is maintained. Data from postmortem tissue and in vivo imaging studies suggest that increased activity of intracellular calcium-independent PLA2 (iPLA2) in the brain of schizophrenic patients might accelerate the breakdown of membrane phospholipids and alter the properties of neuronal membranes, which in turn contributes to a hypodopaminergy. Alterations in PLA2 activity are probably genetically determined and represent a possible pharmacological target for Schizophrenia.
Asunto(s)
Encéfalo/metabolismo , Lípidos de la Membrana/metabolismo , Fosfolipasas A2/metabolismo , Fosfolípidos/metabolismo , Esquizofrenia/metabolismo , Encéfalo/fisiopatología , Dopamina/metabolismo , Humanos , Neuroimagen , Fosfolipasas A2/químicaRESUMEN
In rats, phospholipase A(2) (PLA(2)) activity was found to be increased in the hippocampus immediately after training and retrieval of a contextual fear conditioning paradigm (step-down inhibitory avoidance [IA] task). In the present study we investigated whether PLA(2) is also activated in the cerebral cortex of rats in association with contextual fear learning and retrieval. We observed that IA training induces a rapid (immediately after training) and long-lasting (3 h after training) activation of PLA(2) in both frontal and parietal cortices. However, immediately after retrieval (measured 24 h after training), PLA(2) activity was increased just in the parietal cortex. These findings suggest that PLA(2) activity is differentially required in the frontal and parietal cortices for the mechanisms of contextual learning and retrieval. Because reduced brain PLA(2) activity has been reported in Alzheimer disease, our results suggest that stimulation of PLA(2) activity may offer new treatment strategies for this disease.
Asunto(s)
Reacción de Prevención/fisiología , Corteza Cerebral/enzimología , Condicionamiento Psicológico/fisiología , Recuerdo Mental/fisiología , Fosfolipasas A2/metabolismo , Análisis de Varianza , Animales , Conducta Animal , Corteza Cerebral/anatomía & histología , Electrochoque/métodos , Activación Enzimática/fisiología , Miedo , Modelos Lineales , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
In rats, the inhibition of phospholipase A(2) (PLA(2)) in hippocampus was reported to impair memory acquisition. In the present study we investigated in rats whether PLA(2) inhibition in hippocampus is also related to impairment of memory retrieval. Rats were bilaterally implanted with cannulae in hippocampal CA1 region. After recovery, animals were submitted to one-trial step-down inhibitory avoidance task and tested for long-term memory (LTM) 24 h later. Before test session, animals received infusions of vehicle or the PLA(2) inhibitor PACOCF(3). Inhibition of PLA(2) activity impaired LTM retrieval. Memory impairment was fully reversed once PLA(2) activity was recovered. Moreover, LTM retrieval per se increased PLA(2) activity. To our knowledge, we demonstrated for the first time that PLA(2) activity is required for memory retrieval. Because reduced PLA(2) activity has been found in Alzheimer's disease brains, the present results may be relevant to clarify at least part of the biology of this disorder.
Asunto(s)
Hipocampo/enzimología , Trastornos de la Memoria/enzimología , Memoria/fisiología , Fosfolipasas A/metabolismo , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/fisiopatología , Animales , Ansiedad/inducido químicamente , Ansiedad/enzimología , Ansiedad/fisiopatología , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Hipocampo/efectos de los fármacos , Cetonas/farmacología , Masculino , Memoria/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/fisiopatología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Pruebas Neuropsicológicas , Fosfolipasas A/antagonistas & inhibidores , Fosfolipasas A2 , Ratas , Ratas WistarRESUMEN
Phospholipase A(2) (PLA(2)) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA(2) activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent (31)P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA(2) activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA(2) has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA(2) inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA(2) precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA(2) enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA(2) activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Hipocampo/metabolismo , Memoria/fisiología , Plasticidad Neuronal/fisiología , Neuronas/enzimología , Fosfolipasas A/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Plaquetas/metabolismo , Homeostasis , Humanos , Fosfolipasas A2 , Fosfolípidos/metabolismoRESUMEN
Phospholipase A2 (PLA2) is a family of key enzymes in membrane phospholipid metabolism. In rats, the inhibition of PLA2 activity in the hippocampus was found to impair memory formation. Because memory function is largely dependent on the fluidity of brain membranes, we performed the present study to investigate the effects of in vivo PLA2 inhibition (with PACOCF3) on the fluidity of hippocampal membranes from rats trained in a learning task. Hippocampal tissue from rats injected with 100 microM PACOCF3 showed reduced membrane fluidity as compared to vehicle (p < 0.01), and the reduction of membrane fluidity was highly correlated with PLA2 inhibition (r = .76, p < 0.03). This finding is of interest because reduction of brain membrane fluidity impairs memory formation and both decreased PLA2 activity and reduced membrane fluidity have been reported in the brain from patients with Alzheimer's disease.
Asunto(s)
Hipocampo/enzimología , Fluidez de la Membrana/fisiología , Fosfolipasas A/metabolismo , Animales , Inhibidores Enzimáticos/administración & dosificación , Hipocampo/efectos de los fármacos , Inyecciones Intraventriculares , Cetonas/administración & dosificación , Masculino , Fluidez de la Membrana/efectos de los fármacos , Fosfolipasas A/efectos de los fármacos , Fosfolipasas A2 , Ratas , Ratas WistarRESUMEN
In neurons, phospholipase A2 (PLA2) plays a central role in the regulation of membrane phospholipid metabolism. We have addressed the pharmacological modulation of PLA2 in primary cultures of rat cortical neurons. Inhibition curves were obtained in 4 day-in-culture neurons treated for 30 minutes with either the dual PLA2 inhibitor methyl arachidonyl fluorophosphonate (MAFP), or the iPLA2 inhibitor bromoenol lactone (BEL). Full inhibition was achieved with 100 and 250 microM of MAFP, or 10 and 20 microM of BEL. Conversely, a dose-dependent activation of PLA2 was obtained with 10-20 microg/ml of melitin. PLA2 inhibition with MAFP or BEL was not acutely toxic for cultured neurons. However, sustained inhibition of the enzyme precluded the development of neurites, and resulted in long-term loss of neuronal viability. We present a model of pharmacological challenge of PLA2 in vitro, which can be further used to address the involvement of the enzyme in neurodevelopment and neurodegeneration models.
Asunto(s)
Corteza Cerebral/citología , Neuronas/enzimología , Fosfolipasas A/metabolismo , Fosfolípidos/metabolismo , Animales , Antígenos Bacterianos/farmacología , Ácidos Araquidónicos/farmacología , Membrana Celular/enzimología , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Naftalenos/farmacología , Degeneración Nerviosa/metabolismo , Neuronas/citología , Organofosfonatos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Fosfolipasas A/antagonistas & inhibidores , Fosfolipasas A2 , Embarazo , Pironas/farmacología , Ratas , Ratas WistarRESUMEN
We investigated, with the aid of a radio-enzymatic method, the developmental changes in the activity of 85 kDa calcium-dependent cytosolic phospholipase A(2) (cPLA(2)) in pre-term embryonic rat brain and in primary cultures of cortical neurons. PLA(2) activity was highest in the brains of 18 day embryos (E18) and gradually decreased toward birth (E18 through E21). No significant differences were found regarding cPLA(2) activity in different topographies, namely hippocampus, cortex, and total brain. In primary cultures of E18/E19 cortical neurons, cPLA(2) activity was higher than the respective embryonic tissue activity, straight from early development. In vitro cPLA(2) activity peaked on the 4th day in culture, and decreased after the six days of incubation, when the cultures became mature. This result reinforces previous evidence that cPLA(2) plays an important role in the early development of the nervous system, and further suggests that it may be implicated in neurodevelopmental processes and in in vitro neuronal survival. We believe that we have produced a useful model for the tissue culture study of PLA(2) metabolism and biochemistry, which can be further addressed to the investigation of the biology of neurodegenerative and neuropsychiatric disorders.