Paul J. L. M. Strijbos

Corticotrophin-releasing factor antagonist inhibits neuronal damage induced by focal cerebral ischaemia or activation of NMDA receptors in the rat brain.

This study investigated the involvement of corticotrophin-releasing factor (CRF) in acute neuronal damage induced by focal cerebral ischaemia or pharmacological activation of NMDA receptors in the rat brain. Intracerebroventricular injection of a CRF receptor antagonist (alpha-helical CRF9-41), markedly inhibited ischaemic (61%) and excitotoxic (41%) brain damage. Peripheral injection of a glucocorticoid antagonist (RU38486) did not affect ischaemic damage. Ischaemic and excitotoxic damage caused increased hypothalamic concentrations of CRF. These data indicate that CRF mediates ischaemic and excitotoxic neuronal damage in the rat, but that this effect is not dependent on glucocorticoids.

Localization of immunoreactive lipocortin-1 in the brain and pituitary gland of the rat. Effects of adrenalectomy, dexamethasone and colchicine treatment

The presence and localization of endogenous lipocortin-1 (LC-1, a protein which has been proposed to mediate the anti-inflammatory actions of the glucocorticoids) was studied by immunohistochemical techniques in rat brain and pituitary. A polyclonal antiserum specific for a fragment of lipocortin-1 (alpha alpha 1-188) was used to visualize immunoreactive LC-1 (iLC-1) in both neuronal and non-neuronal cell structures. Neuronal staining, which was independent of microtubular axonal transport mechanisms (in that it was not affected by blockade of axonal transport), was found in varicose nerve fibres in various regions of the brain. In addition, iLC-1 was found in the cytoplasm of neuronal cells throughout the brain. Of all brain regions which showed iLC-1, only the hippocampal neurons showed a reduced staining intensity after adrenalectomy. However, iLC-1 was not affected by dexamethasone treatment. Non-neuronal iLC-1 was found in ependymocytes lining the cerebral ventricles and aqueduct. In addition, iLC-1 was found in tanycytes in all circumventricular organs studied and in the ventral walls of the third ventricle, where some of the branching tail processes appeared to envelop local capillaries and neuronal cell bodies. A tancycyte-mediated release of LC-1 from varicose nerve fibres into the portal vasculature is proposed.

Dietary N-3 fatty acids inhibit ischaemic and excitotoxic brain damage in the rat

Arachidonic acid [20:4(N-6)] has been implicated in neurological damage induced by cerebral ischaemia. Membrane arachidonate concentrations can be reduced by changes in dietary fat intake. Therefore, in the present study, we have investigated the effects of N-3 fatty acid supplementation on neuronal damage induced by permanent focal cerebral ischaemia or pharmacological activation of striatal NMDA receptors. Weanling rats were fed either a control diet or an N-3 supplemented diet (1.75% by weight as N-3 fatty acids) for 6 weeks. N-3-supplemented animals reduced ischaemic damage following middle cerebral artery occlusion (36%, p < 0.05), and excitotoxic damage induced by infusion of the selective NMDA agonist (1-aminocyclobutane-cis-1,3-dicarboxylic acid, 43%, p < 0.001) compared to the control-fed group. These data are consistent with the proposed role of arachidonic acid in ischaemic and excitotoxic brain damage, and suggest that modest dietary supplementation with N-3 fatty acids may offer benefit to populations at high risk of stroke.