Relationship between the Neuroprotective Effect of Na<SUP>+</SUP>/H<SUP>+</SUP> Exchanger Inhibitor SM-20220 and the Timing of Its Administration in a Transient Middle Cerebral Artery Occlusion Model of Rats

Abstract

The aim of this study was to determine the relationship between the neuroprotective effect of SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) and the timing of its administration in an experimental stroke model. Two hours of occlusion followed by 22 h of perfusion of the left middle cerebral artery (MCA) was performed by inserting a nylon thread into the MCA to occlude it, and pulling the thread to initiate reperfusion. Intravenous infusion of SM-20220 for 1 h reduced the infarct volume at doses of 0.2-0.8 mg/kg in a dose-dependent manner without causing changes in the systemic arterial blood pressure or blood gases, when SM-20220 administration was started 1 h after the onset of occlusion. Administration of SM-20220 at a dose of 0.4 mg/kg also reduced the edema formation induced by ischemia. In contrast, SM-20220 failed to reduce the infarction, even at 1.6 mg/kg, when administration was started 2 h after the onset of occlusion. Thus, the therapeutic time window of SM-20220 for this transient MCA occlusion model is 1 h. Daily administration of SM-20220 (0.4 mg/kg) for the 7 d following 1.5 h of middle cerebral artery occlusion reduced the infarct volume with statistical significance ( pϽ0.05), showing that SM-20220 did not merely delay but prevented ischemic damage. Key words Naϩ /H ϩ exchanger; brain ischemia; infarction; SM-20220; edema; therapeutic time window centage of the area of the left hemisphere for each coronal section. The infarct volume was calculated by integration of the infarct areas and the areas of the left hemisphere that were determined for the five coronal sections. Measurement of Arterial Blood Pressure, Gases, and pH In some animals, a femoral artery was cannulated to directly and continuously measure the systemic arterial blood pressure with a pressure transducer (P10EZ, Nihon Kohden, Osaka, Japan) attached to a blood-pressure amplifier (AP-641G, Nihon Kohden) and to sample blood for the analysis of blood gases and pH using I-STAT (Fuso Chemicals, Osaka, Japan). Measurement of Cerebral Water ContentTo measure the brain water content, rats were decapitated 4 h after the onset of reperfusion and the left hemisphere of the occluded MCA territory was cut into 4-mm-thick slices (1 mm anterior-3 mm posterior to the bregma).10) The water content was determined by the dry-weight method. 13)Experimental Protocol The experimental protocol is shown in Fig. 1. SM-20220 was dissolved in 8% polyethylene glycol 400 (w/v) to 0.4 mg/ml and diluted with the same solution to 0.04, 0.08, 0.16, and 0.32 mg/ml. The diluted SM-20220 or just the solution as vehicle was given as an intravenous infusion (5 ml/kg/h) for 1 h using an infusion pump (model 100, KD Scientific, U.S.A.).For the first experiment, the administration of SM-20220 or vehicle was started 1 h after the onset of occlusion, and physiological variables were measured before surgery, before drug administration, and 30 min after the onset of reperfusion; the infarct size was measured 22 h after the onset.For the sec...

Neuroprotective Efficacy of Repinotan HCl, a 5-HT1A Receptor Agonist, in Animal Models of Stroke and Traumatic Brain Injury

“…It is difficult to view our results in the context of other published data, because the techniques, models, administration regimens, and results reported in the literature are highly diverse, as are the mechanisms of action of the tested drugs. Such compounds as ZK200775 (Turski et al, 1998), YM872 (Takahashi et al, 1998), NXY-059 (Sydserff et al, 2002), FK506 (Furuichi et al, 2003), or SM-20220 (Horikawa et al, 2001) attenuate different mechanisms in the pathogenesis of stroke and exhibit therapeutic windows of 2 to 4 hours in either the pMCA-O or tMCA-O model, but were not evaluated in the SDH model. However, when administered as a continuous intravenous infusion, repinotan is the only compound that displays a therapeutic window of at least 5 hours in all models.…”

Disruption of Ion Homeostasis in the Neurogliovascular Unit Underlies the Pathogenesis of Ischemic Cerebral Edema

“…The NHE inhibitor SM-20220 reduces cerebral endothelial dysfunction after 1–7 days of reperfusion following MCAO in the rat [82, 83]. Edema and neutrophil invasion of the area of ischemic injury are reduced by SM-20220 as well [84].…”

Radial glia express aromatase in the injured zebra finch brain

“…There is a detectable difference in pH between astrocytic and neuronal compartments, pH being about 0.1 units higher in astrocytes (Kintner et al, 2000), and astrocytes may protect neurons against glutamate toxicity by acidification of the extraneuronal milieu (Ransom, 2000) via the operation of an inwardly directed Na + /HCO cotransporter (Lascola and Kraig, 1997) with a 1:2 stoichiometric ratio for Na + and bicarbonate (McAlear and Bevensee, 2004). In response to intracellular acidity there is also an increased activity of the Na + /H + exchanger, an ubiquitous transporter exchanging intracellular H + with extracellular Na + , and inhibition of Na + /H + exchange reduces infarct size, when applied within 1 h after the onset of the occlusion (Kuribayashi et al, 1999; Horikawa et al, 2001a, b; Kitayama et al, 2001). Strict management of pH during the first hour after reperfusion also has a beneficial effect (Kollmar et al, 2002a).…”