Research reportAbility of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats
Introduction
Stroke is a major cause of death and disability in the elderly. Although several neuroprotectants have been developed in clinical trials, few are in fact clinically effective [1], [2]. Elevated extracellular glutamate after cerebral ischemia is thought to play a key role in the development of cerebral infarction via N-methyl-d-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors [15]. Although NMDA and AMPA receptor antagonists reduce ischemic damage in stroke models of young animals [8], [10], these agents have been ineffective in clinical trials of acute stroke [1], [2]. The inhibitory effects of neuroprotectants have been investigated in preclinical studies using cerebral ischemic models of young animals. Yet, patients who present with acute stroke are usually elderly. These findings suggest that data obtained from preclinical studies using young animals may not accurately reflect results in aged humans, because aging probably affects physiological functions. Thus, the present study investigated the inhibitory effects of the NMDA antagonist MK-801 and the AMPA receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinixaline] on ischemic cerebral damage in a model of middle cerebral artery (MCA) thrombotic occlusion using aged and young rats. We stereotaxically injected NMDA and kainic acid, which are agonists of NMDA and AMPA receptors, respectively, into the cortex of aged and young rats and evaluated cerebral damage. Thrombotic MCA occlusion in the rat induced by photochemical means is a model of focal cerebral ischemia [9], [12], [13], [14] in which the neuroprotective effects of several compounds have been tested. One unique aspect of this model is that it has the characteristics of both permanent ischemia and ischemia-reperfusion. This has been demonstrated by an autoradiographic study in which the change in cerebral blood flow in the ischemic border zone resembled a reperfusion-like phenomenon [13].
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Animal preparation
Young (8 weeks old) and aged (24 months) (SLC, Japan) male Sprague–Dawley rats weighing 250–320 and 450–700 g, respectively, underwent surgical procedures at 37.5±0.5 °C (maintained with a K-module Model K-20 heating pad; American Pharmaseal, USA). All experiments were performed in accordance with the institutional guidelines of the Hamamatsu University School of Medicine.
The animals were anesthetized with 4% halothane and maintained with 2% halothane in 30% oxygen and 70% room air. A plastic
Results
Physiological variables following surgery were within normal ranges (Table 1). Blood pH of aged rats before rose bengal injection was slightly lower than that of young rats. Heart rate of aged rats after the MCA occlusion slightly decreased compared with young rats.
MK-801 or NBQX at the doses described above did not affect rectal and brain temperature, and temperature did not differ significantly between aged and young rats (Table 2).
Discussion
The present study found that receptor antagonists for both AMPA and NMDA reduced cerebral damage in young, but not in aged, rats. We administered MK-801 and MBQX at doses of 0.1 and 30 mg/kg, respectively, to investigate their neuroprotective effects. These doses are the maximal levels that can be applied in vivo without side effects and which are supposedly effective in young ischemic models [3], [12]. Microinjection of kainic acid into brain tissue elicited a fatal outcome in the aged, but
References (16)
- et al.
The neuroprotective actions of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) in a rat focal ischaemia model
Brain Res.
(1992) - et al.
Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats
Neurobiol. Aging
(1999) - et al.
In vivo microscopic studies of age-related changes in the structure and the reactivity of cerebral microvessels
Mech. Ageing Dev.
(1992) - et al.
Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion
Brain Res.
(2000) - et al.
Neuroprotective effects depend on the model of focal ischemia following middle cerebral artery occlusion
Eur. J. Pharmacol.
(1998) - et al.
Change of local cerebral blood flow in photochemically-induced thrombotic occlusion model in rats
Eur. J. Pharmacol.
(2000) - et al.
Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist
Stroke
(2000) - et al.
An overview of acute stroke therapy: past, present, and future
Arch. Intern. Med.
(2000)
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