RESUMEN
A general consensus is being reached on the use of a combination of mortality and functional end-points in clinical trials of neuroprotective agents. However, to date, few preclinical studies have examined the effects of putative neuroprotective agents on functional outcome after ischaemia. The data described in this review show the importance of combining both histopathological and neurobehavioural studies when evaluating the neuroprotective efficacy of anti-ischaemic agents in animal models of cerebral ischaemia. Here, Jackie Hunter, Ken Mackay and Derek Rogers argue that measures of functional improvement in models of ischaemia should be incorporated to characterize further the neuroprotection afforded by a compound that could aid the selection of doses and end-point measures in early clinical trials.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Encéfalo/patología , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Isquemia Encefálica/fisiopatología , Trastornos Cerebrovasculares/tratamiento farmacológico , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Ataque Isquémico Transitorio/tratamiento farmacológico , Ratones , Desempeño Psicomotor/efectos de los fármacos , RatasRESUMEN
The neuroprotective effects of a systemically active, highly selective, corticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipropylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] pyrimidine), was assessed in two rat models of permanent focal cerebral ischemia, where the middle cerebral artery (MCA) was occluded either through the subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood-brain barrier after intravenous (IV) bolus administration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 +/- 0.40 microg/mL), which were approximately 2-fold greater than those in plasma (0.98 +/- 0.24 microg/mL). Treatment with R121920 (10 mg/kg IV followed by 5 mg/kg subcutaneously at hourly intervals for 4 hours) significantly (P < 0.001) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO model, IV administration of R121920 (10 mg/kg) at the time of ischemia onset (and at multiple times thereafter) reduced both hemispheric infarct volume (by 34%, P < 0.001) and brain swelling (by 50%, P < 0.001) when assessed at 24 hours. In this model of focal ischemia, significant reduction (P < 0.05) in both outcome measures was obtained when R121920 administration was delayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF 1 antagonists in two experimental models of permanent focal cerebral ischemia.
Asunto(s)
Isquemia Encefálica/fisiopatología , Fármacos Neuroprotectores/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Edema Encefálico/fisiopatología , Edema Encefálico/prevención & control , Masculino , Arteria Cerebral Media/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Whether atrial natriuretic peptide (ANP)-evoked inhibition of corticotrophin-releasing factor (CRF)-stimulated ACTH secretion was also manifest in ACTH secreting AtT-20 pituitary tumour cells was investigated. ANP stimulated increases in cGMP accumulation at concentrations of the peptide above 10(-8) M which indicates the presence of the ANP receptors on these cells. CRF stimulated a concentration-dependent increase in ACTH secretion from AtT-20 cells which was unaffected by ANP, 8-bromo-cGMP, or sodium nitroprusside (SNP). Calcium stimulated a concentration-dependent increase in ACTH secretion from electrically permeabilised cells which was unaffected by co-incubation with cGMP but potentiated by cAMP. These results reveal the presence of ANP receptors on AtT-20 cells but suggest that an incomplete expression of the stimulus-secretion coupling mechanisms for ANP, at some point after cGMP production, prevents the effects of natriuretic peptides upon ACTH secretion being manifest in these cells.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Factor Natriurético Atrial/farmacología , Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Neoplasias Hipofisarias/patología , 1-Metil-3-Isobutilxantina/farmacología , Animales , Calcio/farmacología , Permeabilidad de la Membrana Celular , Hormona Liberadora de Corticotropina/farmacología , AMP Cíclico/farmacología , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , GMP Cíclico/farmacología , Sistema Hipotálamo-Hipofisario/fisiología , Ratones , Nitroprusiato/farmacología , Neoplasias Hipofisarias/metabolismo , Receptores del Factor Natriurético Atrial/efectos de los fármacos , Receptores del Factor Natriurético Atrial/metabolismo , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
BMS-204352 is a fluoro-oxindole potassium channel opener being developed by Bristol-Myers Squibb as a potential neuroprotectant for the treatment of acute ischemic stroke. Phase I trials were underway in Japan in 1998 [288541]. By July 1999, it was in phase II trials in the US [331682] and by October 2000, phase II trials had also begun in Japan [384751]. At the 219th American Chemical Society meeting in March 2000, it was reported that BMS-204352 had entered worldwide phase III trials involving patients with suspected acute stroke [362077], [361291]. In February 2001, Credit Suisse First Boston predicted sales of $111 million in 2005 [399484]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2004. The analysts predicted peak sales would occur in 2008, with sales of $500 million in the US at that time [319225].
Asunto(s)
Indoles/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Enfermedad Aguda , Animales , Ensayos Clínicos como Asunto , Contraindicaciones , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Indoles/farmacología , Indoles/toxicidad , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/toxicidad , Accidente Cerebrovascular/psicología , Relación Estructura-ActividadRESUMEN
The effects of the kappa-opioid agonist CI-977 upon local cerebral glucose utilization have been examined in conscious, lightly restrained rats to gain insight into the potential adverse effects of this neuroprotective agent. Cerebral glucose utilization was assessed quantitatively in 45 anatomically discrete brain regions by means of [14C]2-deoxyglucose autoradiography. The i.v. administration of CI-977 (0.03-3 mg/kg) induced relatively homogeneous patterns of altered cerebral glucose utilization with moderate statistically significant reductions (approximately 25%) being observed in 29 brain regions, and a statistically significant increase (approximately 40%) in one brain region, the lateral habenular nucleus. Glucose use throughout the entire neocortex and inferior colliculus was particularly sensitive to reduction (approximately 35%) following CI-977 administration, although there was only a limited dose dependency to the response. Minimal alterations in glucose use were observed in 15 of the 45 brain regions, particularly in the lower brain stem (e.g. superior olives, cochlear nucleus and median raphe) and forebrain limbic regions (e.g. septal nucleus, nucleus accumbens and mediodorsal thalamus). These data demonstrate that CI-977 produces widespread, anatomically organized alterations in function-related glucose use which contrast those seen previously with the NMDA receptor antagonists, thereby suggesting that CI-977 may be intrinsically safer as an in vivo neuroprotective agent.
Asunto(s)
Benzofuranos/farmacología , Encéfalo/efectos de los fármacos , Glucosa/metabolismo , Pirrolidinas/farmacología , Receptores Opioides kappa/efectos de los fármacos , Animales , Corteza Auditiva/efectos de los fármacos , Autorradiografía , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Desoxiglucosa , Tractos Extrapiramidales/efectos de los fármacos , Sistema Límbico/efectos de los fármacos , Masculino , Vaina de Mielina/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/efectos de los fármacos , Corteza Visual/efectos de los fármacosRESUMEN
The effect of a novel, highly potent and selective kappa-opioid receptor agonist CI-977 upon ischaemic brain damage and brain swelling has been examined in a rat model of focal cerebral ischaemia. Focal ischaemia was produced by the permanent occlusion of the left middle cerebral artery (MCA) during a brief period of halothane anaesthesia. The animals were sacrificed 24 h after MCA occlusion and the amount of ischaemic brain damage and swelling was assessed in coronal sections at 8 predetermined stereotactic planes. Treatment with CI-977 (0.03, 0.3 or 3 mg/kg), initiated 30 min prior to MCA occlusion (and at multiple times thereafter) produced dose-dependent reductions in the volumes of infarction and of brain swelling, with the most marked reductions being noted with CI-977 (0.3 mg/kg) in both infarction (reduced by 38% from controls; P less than 0.02) and swelling (reduced by 31%; P less than 0.002). There was an excellent correlation between the volume of brain swelling and ischaemic damage which was similar with saline-treated and CI-977-treated animals (overall correlation coefficient r = 0.896). These results indicate that CI-977 is effective in reducing infarction in a model of focal cerebral ischaemia, and that the reduction in brain swelling occurs in parallel with the reduction in ischaemic damage.
Asunto(s)
Benzofuranos/farmacología , Edema Encefálico/prevención & control , Infarto Cerebral/prevención & control , Ataque Isquémico Transitorio/fisiopatología , Pirrolidinas/farmacología , Receptores Opioides/fisiología , Animales , Modelos Animales de Enfermedad , Ataque Isquémico Transitorio/patología , Masculino , Ratas , Ratas Endogámicas , Receptores Opioides/efectos de los fármacos , Receptores Opioides kappaRESUMEN
The effects of the kappa-1 opioid agonist CI-977 upon the volume of ischemic brain damage (defined using quantitative neuropathology) and local cerebral blood flow (CBF) (defined using quantitative [14C]iodoantipyrine autoradiography) have been examined at 4 h and 30 min, respectively, after permanent middle cerebral artery (MCA) occlusion in halothane-anesthetised rats. Treatment with CI-977 (0.3 mg/kg, s.c.) 30 min before and 30 min after occlusion of the MCA reduced the volume of infarction in the cerebral hemisphere (reduced by 27% when compared to vehicle; P < 0.05) and cerebral cortex (reduced by 32%; P < 0.05), despite a marked and sustained hypotension, with only minimal effect on damage in the caudate nucleus. In the hemisphere contralateral to the occluded MCA, treatment with CI-977 (0.3 mg/kg, s.c.) 30 min prior to the induction of ischemia failed to demonstrate any significant effect on either the level of local CBF in any of the 25 regions examined or on the volume of low CBF determined by frequency distribution analysis. In the hemisphere ipsilateral to MCA occlusion, CI-977 failed to produce statistically significant alterations in either the level of local CBF in 23 of the 25 regions or on the volume of low CBF, but areas of hyperemia were observed in both the medial caudate nucleus and lateral thalamus (local CBF increased by 65% and 86%, respectively, when compared to vehicle).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Benzofuranos/farmacología , Isquemia Encefálica/fisiopatología , Encéfalo/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Pirrolidinas/farmacología , Receptores Opioides kappa/fisiología , Animales , Antipirina/análogos & derivados , Antipirina/metabolismo , Autorradiografía , Presión Sanguínea/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Isquemia Encefálica/patología , Arterias Cerebrales , Lateralidad Funcional , Radioisótopos de Yodo , Masculino , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/efectos de los fármacos , Factores de TiempoRESUMEN
The alterations in Alzheimer's disease (AD) of two binding sites in the striatum suggested to have a presynaptic localisation have been investigated by quantitative ligand binding autoradiography. Adenosine A1 binding sites labelled with [3H]cyclohexyladenosine (CHA) and kappa 1 opioid binding sites labelled with [3H]U-69593 were studied in adjacent sections of the striatum obtained postmortem from 10 patients with AD and 9 matched controls. In AD, there was a significant reduction of [3H]CHA binding sites in the caudate nucleus (control = 88 +/- 4; AD = 56 +/- 6 pmol/g tissue; mean +/- S.E.M.) and putamen (control = 83 +/- 4; AD = 58 +/- 7 pmol/g). In control subjects, highest levels of [3H]U-69593 binding were localised to patches within the caudate nucleus (9.66 +/- 0.58 pmol/g) with lower levels in the matrix (5.54 +/- 0.48 pmol/g). There was no alteration in [3H]U-69593 binding sites in either the caudate nucleus (patches and matrix) or putamen of AD patients. The activity of choline acetyltransferase (ChAT), determined in the same tissue samples used for autoradiographic analysis, was significantly reduced in AD (control = 124 +/- 11; AD = 64 +/- 14 nmol/h/mg protein). There was a positive correlation between ChAT activity and [3H]CHA binding (r = 0.769), but not [3H]U-69593 binding (r = 0.197). The results indicate that a marked loss of adenosine A1 receptors occurs in the striatum of AD with no loss of kappa 1 opioid receptors, and that the loss of A1 receptors parallels the loss of choline acetyltransferase activity.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Bencenoacetamidas , Cuerpo Estriado/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Purinérgicos/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Analgésicos/metabolismo , Autopsia , Autorradiografía , Núcleo Caudado/metabolismo , Núcleo Caudado/patología , Colina O-Acetiltransferasa/análisis , Colina O-Acetiltransferasa/metabolismo , Cuerpo Estriado/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Putamen/metabolismo , Pirrolidinas/metabolismo , Valores de Referencia , TritioRESUMEN
The effects of the kappa-1 opioid receptor agonist (5R)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-4- benzofuranacetamide monohydrochloride (CI-977) upon ischemic brain damage have been examined in 15 halothane-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery (MCA), and the animals killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotactic planes. Pretreatment with CI-977 (0.3 mg/kg i.v. followed by continuous infusion at 0.15 mg/kg/h until death), initiated 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 2345 +/- 675 mm3 of the cerebral hemisphere in vehicle-treated cats to 1569 +/- 370 mm3 in CI-977-treated cats; P < 0.01). These data indicate that the kappa-1 opioid agonist CI-977 is neuroprotective in a model of focal cerebral ischemia in a gyrencephalic species where key systemic variables have been assessed throughout the entire post-ischemic period.
Asunto(s)
Benzofuranos/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Receptores Opioides kappa/fisiología , Animales , Benzofuranos/sangre , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Encéfalo/patología , Gatos , Arterias Cerebrales/fisiología , Hematócrito , Histocitoquímica , Ataque Isquémico Transitorio/patología , Ataque Isquémico Transitorio/fisiopatología , Pirrolidinas/sangreRESUMEN
The ability of five agents (dizocilpine [MK-801], 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline [NBQX], enadoline [CI-977], L-nitroarginine methyl ester [L-NAME] and BW 1003c87) with well defined, distinct pharmacological profiles and with established anti-ischemic efficacy, to modify neuronal damage has been examined in a simple in vivo model of glutamate excitotoxicity. Cortical lesions were produced in physiologically-monitored halothane-anesthetised rats by reverse dialysis of glutamate. The volume of the lesion was quantified histologically by image analysis of approximately 20 sections taken at 200 microm intervals throughout the lesion. The AMPA and NMDA receptor antagonists (NBQX and MK-801) and the inhibitor of nitric oxide synthase (L-NAME) significantly reduced the lesion volume by a similar extent (by approximately 30% from vehicle). Two agents (the kappa opioid agonist, CI-977 and the sodium channel blocker, BW 1003c87) which putatively inhibit the release of endogenous glutamate presynaptically, had dissimilar effects on lesion size. CI-977 failed to alter the amount of damage produced by exogenous glutamate, whereas BW 1003c87 reduced the lesion size by approximately 50%. Using this model, the neuroprotective effects of anti-ischemic drugs can be explored in vivo, uncomplicated in contrast to experimental ischemia by reduced oxygen delivery, drug effects on tissue blood flow and compromised energy generation. In consequence, additional mechanistic insight into anti-ischemic drug action in vivo can be obtained.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Corteza Cerebral/patología , Antagonistas de Aminoácidos Excitadores , Glutamatos/toxicidad , Neuronas/patología , Neurotoxinas/toxicidad , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Animales , Arginina/análogos & derivados , Arginina/farmacología , Benzofuranos/farmacología , Isquemia Encefálica/prevención & control , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Maleato de Dizocilpina/farmacología , Ácido Glutámico , Masculino , Microdiálisis , NG-Nitroarginina Metil Éster , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neurotoxinas/antagonistas & inhibidores , Óxido Nítrico Sintasa , Pirimidinas/farmacología , Pirrolidinas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The effect of the kappa-opioid agonist enadoline (CI-977) upon the relationship between cerebral blood flow and glutamate release was simultaneously assessed (using microdialysis and hydrogen clearance techniques respectively) at the same anatomical locus in the cerebral cortex (suprasylvian gyrus) after permanent middle cerebral artery (MCA) occlusion in halothane-anaesthetised cats. During controlled graded ischaemia, pretreatment with enadoline (0.3 mg/kg i.v. followed by continuous infusion at 0.15 mg/kg/h), initiated 30 min prior to MCA occlusion, significantly attenuated the marked increases in extracellular glutamate, aspartate and GABA observed in the focal ischaemic penumbra. The present data are consistent with the hypothesis that the neuroprotective efficacy of enadoline in focal cerebral ischaemia is due to inhibition of glutamate release in the ischaemic penumbra.
Asunto(s)
Antiarrítmicos/farmacología , Benzofuranos/farmacología , Isquemia Encefálica/fisiopatología , Circulación Cerebrovascular/efectos de los fármacos , Ácido Glutámico/metabolismo , Pirrolidinas/farmacología , Receptores Opioides kappa/agonistas , Animales , Glucemia/metabolismo , Temperatura Corporal/efectos de los fármacos , Isquemia Encefálica/metabolismo , Gatos , Femenino , Microdiálisis , Técnicas Estereotáxicas , Tirosina/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Indanos/farmacología , Fármacos Neuroprotectores/farmacología , Bloqueadores de los Canales de Sodio , Accidente Cerebrovascular/prevención & control , Anestesia , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Estenosis Carotídea/fisiopatología , Estenosis Carotídea/prevención & control , Células Cultivadas , Estado de Conciencia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Gerbillinae , Hemodinámica/efectos de los fármacos , Hipertensión/fisiopatología , Indanos/farmacocinética , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/prevención & control , Ataque Isquémico Transitorio/fisiopatología , Ataque Isquémico Transitorio/prevención & control , Masculino , Potenciales de la Membrana/efectos de los fármacos , Tasa de Depuración Metabólica , Ratones , Actividad Motora/efectos de los fármacos , Neuronas Aferentes/citología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Accidente Cerebrovascular/fisiopatología , Distribución TisularRESUMEN
This study investigated the immunostaining of protein kinase C (PKC) isoforms and amyloid precursor protein (APP) in rat brain cortex and determined alterations following an excitotoxic challenge in vivo. Cellular alterations in APP and PKC isoforms (alpha, beta, gamma, delta, epsilon, and zeta) following glutamate perfusion in the rat parietal cortex were compared with NaCl perfusion. In all animals, two histological zones could be defined consistently, a necrotic core and a boundary zone immediately adjacent to the core. Following glutamate and NaCl perfusion, cellular immunoreactivity to PKC isoforms and amino-terminal APP was significantly reduced within the necrotic core. Striking carboxy-terminal APP immunoreactivity was observed in some neurons remaining within the necrotic core. In the boundary of the glutamate lesion, the perikarya of most neurons were intensely immunoreactive to PKC alpha and beta. Furthermore, within the boundary zone, enhanced immunoreactivity within neuronal perikarya was observed to amino-terminal APP and, to a lesser extent, carboxy-terminal APP. Increased immunostaining of PKC alpha and beta and APP at the boundary zone was a consistent feature of intracortical glutamate perfusion and was not observed following NaCl perfusion. There were minimal alterations in PKC isoforms gamma, delta, epsilon, and zeta, in the boundary region following intracortical glutamate or NaCl perfusion. There was no astrocytic response, as detected by GFAP immunoreactivity, at the boundary zone. These findings indicate that there is a topographical relationship between cellular alterations of specific PKC isoforms and APP following an excitotoxic challenge in vivo.
Asunto(s)
Precursor de Proteína beta-Amiloide/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Ácido Glutámico/farmacología , Proteína Quinasa C/efectos de los fármacos , Animales , Inmunohistoquímica , Técnicas In Vitro , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The binding of [3H]-U-69593 and [3H]-CI-977 to kappa-1 opioid receptors has been examined in the temporal cortex of postmortem brains from patients with Alzheimer's disease and age-matched controls using quantitative autoradiography. There was no significant difference between Alzheimer and control subjects in the level of [3H]-U-69593 and [3H]-CI-977 binding, but ChAT activity was markedly reduced (by 73% compared to controls). These results are not consistent with a presynaptic localisation of kappa-1 receptors on cholinergic terminals in human temporal cortex.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Bencenoacetamidas , Receptores Opioides kappa/metabolismo , Lóbulo Temporal/metabolismo , Anciano , Autorradiografía , Unión Competitiva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinas/farmacología , Receptores Opioides kappa/antagonistas & inhibidoresRESUMEN
BACKGROUND AND PURPOSE: There have been a number of recent reports describing the relationship between ischemic damage and various behavioral and functional measures, although there have been few studies that have demonstrated a direct correlation between functional impairment and lesion volume. The purpose of the present study was to assess functional outcome by measurement of motor impairment and to determine whether this correlated to a range of infarct volumes induced by varying the duration of focal ischemic insult in the rat. METHODS: Male Sprague Dawley rats were subjected to 0, 30, 60, of 120 minutes or permanent middle cerebral artery (MCA) occlusion by the intraluminal filament technique. Motor impairment was assessed by the accelerating rota-rod and grid-walking tests, and the brains were perfusion-fixed for histological determination of infarct volume and brain swelling 24 hours after MCA occlusion. RESULTS: Marked impairment in performance of both motor tests was recorded in the 60-minute, 120-minute, and the permanent MCA occlusion groups when compared with sham-operated rats. There were significant correlations between regional infarct volume, brain swelling, and all behavioral measurements (all r2 > .5, P < .001). CONCLUSIONS: The rota-rod and grid-walking tests of motor performance provide quantitative, objective, and reproducible measures of functional impairment of rats following an ischemic insult. These impairments correlate directly with infarct volume and provide information integral to future studies evaluating the effects of potential neuroprotective agents.
Asunto(s)
Arteriopatías Oclusivas/patología , Arteriopatías Oclusivas/fisiopatología , Arterias Cerebrales , Infarto Cerebral/patología , Infarto Cerebral/fisiopatología , Actividad Motora/fisiología , Enfermedad Aguda , Animales , Arteriopatías Oclusivas/psicología , Conducta Animal/fisiología , Encéfalo/patología , Edema Encefálico/etiología , Infarto Cerebral/psicología , Enfermedad Crónica , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The neuroprotective effects of recombinant neutrophil inhibitory factor (NIF) have been assessed with temporary (2 h) middle cerebral artery (MCA) occlusion in the rat using the intraluminal suture technique. Administration of NIF (1.5 mg/kg, i.v.) immediately after the onset of reperfusion and at 4 and 6 h post-MCA occlusion significantly reduced both hemispheric infarct volume (P < 0.001) and brain swelling (P < 0.001), and improved neurological outcome (P < 0.02) when assessed at 24 h. These results demonstrated the marked neuroprotective efficacy of NIF in a rat model of transient focal cerebral ischaemia.
Asunto(s)
Glicoproteínas/farmacología , Proteínas del Helminto/farmacología , Ataque Isquémico Transitorio/patología , Proteínas de la Membrana , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/efectos de los fármacos , Edema Encefálico/patología , Infarto Cerebral/patología , Masculino , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes , ReperfusiónRESUMEN
Permanent or transient focal cerebral ischemia was induced in spontaneously hypertensive rats (SHR) using the intraluminal filament method. Successful occlusion of the middle cerebral artery (MCA) was achieved using 4/O filaments (terminal diameter 0.20-0.25 mm) coated with poly-L-lysine. The L-type calcium channel blocker isradipine (2.5 mg/kg) administered subcutaneously 30 min following permanent MCA occlusion significantly reduced the volume of ischemic brain damage in the cerebral hemisphere (25%; P = 0.0001), cerebral cortex (18%; P = 0.0034), and caudate nucleus (33%; P = 0.0002) when assessed at 24 h post-MCA occlusion. Isradipine did not affect the functional deficit (measured using a subjective neurological scoring system) induced by MCA occlusion. In SHR undergoing transient (2 h) MCA occlusion isradipine administered 30 min post-MCA occlusion produced a significant reduction (47%; P = 0.001) in hemispheric infarct volume, whereas isradipine administered at the onset of reperfusion did not confer any significant neuroprotection. No change in functional deficit was seen with isradipine with either dosing paradigm at 24 h post-MCA occlusion. These results demonstrate that the intraluminal filament method of MCA occlusion can be used in the SHR strain and also substantiates the neuroprotective efficacy of isradipine in SHR models of permanent and transient focal cerebral ischemia.