Ability of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats

doi:10.1016/S0006-8993(02)04088-X

Brain Research

Volume 964, Issue 1, 21 February 2003, Pages 116-120

https://doi.org/10.1016/S0006-8993(02)04088-X Get rights and content

Abstract

Although stroke is a major cause of death and disability in the elderly, the inhibitory effects of neuroprotectants in acute stroke have been investigated using experimental cerebral ischemic models of young animals. Recent clinical trials have found that few neuroprotectants are effective. These observations indicate that effects in the clinical setting do not always reflect data from young animals. Thus, we compared the effects of the NMDA receptor antagonist MK-801 and of the AMPA receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinixaline] on ischemic cerebral damage in the photothrombosis model of aged and young rats. MK-801 administered immediately after MCA occlusion significantly (P<0.05) reduced the extent of cerebral damage in young, but not in aged, rats and the effects of NBQX were similar. In separate experiments, we evaluated brain damage after microinjecting NMDA or kainic acid into the cortex using a stereotaxic apparatus. We found no significant differences in focal cerebral damage caused by NMDA between young and aged rats. On the other hand, kainic acid caused all of the aged rats tested to die, but none of the young rats. Our observations indicate that NMDA and AMPA receptor antagonists are less effective in aged, than in young, rats and that cerebral damage by receptor agonists depends on the type of receptor, such as NMDA and AMPA.

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].

Section snippets

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

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Furthermore, some drugs showing neuroprotective effects in young rats were ineffective in aged animals. For example, treatment of rats, subjected to photothrombosis, with the N-methyl-d-aspartate antagonist MK-801 was effective in young rats but not in aged animals (Suzuki et al., 2003). A weakness of our study is that we have assessed the effects of IGF-I at a relatively short time point after the insult (24 h), whereas long-term effects are required for effective treatment of patients.
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Research reportAbility of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats

Abstract

Introduction

Section snippets

Animal preparation

Results

Discussion

Brain Res.

Neurobiol. Aging

Mech. Ageing Dev.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Selfotel in acute ischemic stroke: possible neurotoxic effects of an NMDA antagonist

Stroke

An overview of acute stroke therapy: past, present, and future

Arch. Intern. Med.

Research report
Ability of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats