Biomedical subjects

B S Meldrum

Publications and source records attributed to B S Meldrum.

311 records · Page 18Linked to original sources

PubMedDate not supplied

Excitotoxic mechanisms in hypoglycaemic hippocampal injury.

Light and electron microscopy were used to study the effect of hypoglycaemia on selectively vulnerable neurons of rat hippocampus with and without pharmacologic blockade of the N-methyl-D-aspartate (NMDA)-preferring receptor with 2-amino-7-phosphonoheptanoic acid (AP-7). In control hypoglycaemic hippocampi, dark cell change occurs predominantly in dentate granule cells. The topography and ultrastructural appearance of these changes is distinct from that produced by ischaemia or status epilepticus. In hypoglycaemia, mitochondrial calcium accumulation characteristic of ischaemia or status epilepticus is not seen. NMDA receptor blockade markedly attenuates the hypoglycaemic cell injury. Similar attenuation of ischaemic and epileptic brain damage by NMDA receptor blockade suggest that excessive neuronal excitation is a common mechanism of injury in each of the three conditions.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Neuronal alterations in hippocampus following severe hypoglycaemia: a light microscopic and ultrastructural study in the rat.

Because they induce similar neuropathological changes (ischaemic cell change with microvacuolization), it has been suggested that ischaemia, status epilepticus and hypoglycaemia produce cell death by similar mechanisms, especially those resulting from intracellular calcium accumulation. We have recently demonstrated microvacuolation of neurons, mitochondrial swelling (the electron microscopic correlate of microvacuolization) and massive mitochondrial calcium sequestration (using the pyroantimonate technique) following ischaemia or status epilepticus. We therefore studied the selectively vulnerable neurons of rat hippocampus by light and electron microscopy (including the pyroantimonate technique) following 30 and 60 min of EEG isoelectricity resulting from insulin hypoglycaemia. The neuropathology at the light and EM level is unique and different from that following status epilepticus or ischaemia. The most constant finding is dark cell change of the granule cells at the tip of the dentate gyrus. In contrast to status epilepticus and ischaemia, hippocampal pyramidal neurons are far less frequently involved. Microvacuoles are rarely seen and, when present, their ultrastructural correlate is swollen Golgi apparatus, not dilated mitochondria. No intracellular calcium accumulation is demonstrable with pyroantimonate technique. Thus the cellular alterations produced by hypoglycaemia differ in character and distribution from those produced by anoxia-ischaemia. Mitochondrial calcium accumulation is not prominent in cell death from hypoglycaemia. Whether calcium toxicity plays another, subtler role in hypoglycaemic brain injury is unknown.

Animals↗

PubMedDate not supplied

Anticonvulsant activity of two orally active competitive N-methyl-D-aspartate antagonists, CGP 37849 and CGP 39551, against sound-induced seizures in DBA/2 mice and photically induced myoclonus in Papio papio.

Two novel N-methyl-D-aspartate (NMDA) antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid CPG 37849 and the corresponding 1-ethyl ester CGP 39551, were tested as anticonvulsants in DBA/2 mice and photosensitive Senegalese baboons, Papio papio. In DBA/2 mice, CGP 37849 is more potent than CGP 39551 when administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) (ED50 for suppression of clonic seizures at 60 min: i.c.v. 0.038 and 0.21 nmol; i.p. 3.40 and 19.1 mumol/kg, respectively). When administered orally in mice, the two compounds are approximately equipotent (ED50 CGP 37849, 35.2 mumol/kg; ED50 CGP 39551, 28.1 mumol/kg). The time course of action of CGP 39551 is exceptionally prolonged: 42 mumol/kg i.p. protects against clonic seizures for 48 h. Protection provided by other NMDA antagonists in mice is of much shorter duration: 2-amino-5-phosphono-pentanoic acid (AP5) 1 h, 2-amino-7-phosphono-heptanoic acid (AP7) 4 h, 2-amino-7-phosphono-heptanoic acid 1-ethyl ester 3 h, 4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) 2 h, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) 4 h, and CGP 37849 4 h. After oral administration of the drugs, the therapeutic index (TI = ratio of the ED50 values for rotorod performance and anticonvulsant protection) remains relatively constant at 5.9-7.2 for 3 h (CGP 37849) and 4.0-6.1 for 24 h (CGP 39551). After i.p. administration, the TI values are CGP 37849 at 1 h 2.4, and at 3 h 20.0, CGP 39551 at 1 h 2.3, at 3 h 7.1, and at 24 h 3.6. In baboons, acute administration of CGP 37849 at doses of 48-191 mumol/kg intravenously (i.v.) suppresses photically induced myoclonus for at least 285 min, with severe side effects at the highest dose tested. CGP 39551 at doses of 169-675 mumol/kg i.v. shows weak anticonvulsant activity only at the highest dose tested (accompanied by severe side effects). CGP 37849 at 48-96 mumol/kg orally (p.o.) fails to protect against photically induced myoclonus up to 4 h after administration, but 191 mumol/kg (40 mg/kg) p.o. produces complete suppression of seizures after 24 h. On the other hand, CGP 39551 at 169 mumol/kg (40 mg/kg) p.o. produces total suppression of seizure activity at 4 h with a longer duration of anticonvulsant action (2-3 days).(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Regional cerebral blood flow in the rat as determined by particle distribution and by diffusible tracer.

Measurements of total and regional cerebral blood flow in paralyzed rats maintained on 70% N2O/30% O2 obtained by a diffusible tracer technique, iodoantipyrine, and by a particle distribution method, microspheres, have been compared. Total CBF values were in good agreement, 0.86 +/- 0.07 ml/g/min (PaCO2 37.3 +/- 1.5, iodoantipyrine method) and 0.88 +/- 0.02 (PaCO2 36.2 +/- 0.8, microsphere method). Regional cerebral blood flows showed good agreement with the 2 methods, with highest flow in the colliculi, striatum and cerebral cortex and lowest flows in the hypothalamus, pons medulla and cerebellum. The iodoantipyrine method is technically easier to perform and had a higher precision.

Animals↗

PubMedDate not supplied

Cerebroprotective effect of a non-N-methyl-D-aspartate antagonist, NBQX, after focal ischaemia in the rat.

The cerebroprotective effect of the non-N-methyl-D-aspartate antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline.NA) on neurological deficit and infarct volume (visualised with 2,3,5-triphenyltetrazolium) 24 h after permanent middle cerebral artery (MCA) occlusion in Fischer rats (n = 6 per dose) was studied. NBQX (10, 20 or 30 mg Kg-1, i.p., 0,30,60 min) immediately after MCA occlusion reduced cortical infarct volume by 45% (not significant), 70% (p < 0.05) or 75% (p < 0.05) respectively. NBQX (30 mg Kg-1, i.p., 60, 90, 120 min) reduced cortical infarct volume by 58% (p < 0.05). With a 2 h delay NBQX was ineffective. Neurological deficits (with blinded assessment) were improved with immediate or delayed NBQX (3 x 30 mg Kg-1, i.p.). The main adverse behavioral effect of NBQX (3 x 20 or 3 x 30 mg Kg-1, p.i.) was ataxia. The cerebroprotective effect of NBQX in rats suggests a possible therapeutic role for non-N-methyl-D-aspartate antagonists given shortly after stroke onset.

Animals↗