Tizanidine is an effective agent in the prevention of focal cerebral ischemia in rats: an experimental study

Ischemia

Tizanidine is an Effective Agent in the Prevention of Focal Cerebral Ischemia In Rats: An Experimental Study M. Zafer Berkman, M.D.,* T. Ali Zirh, M.D.,† Kemal Berkman, M.D.,§ and M. Necmettin Pamir, M.D.† *Department of Neurosurgery, SSK Okmeydanı Hospital, Departments of †Neurosurgery and §Pharmacology, Marmara University Faculty of Medicine, Istanbul, Turkey

Berkman MZ, Zirh TA, Berkman K, Pamir MN. Tizanidine is an effective agent in the prevention of focal cerebral ischemia in rats: an experimental study. Surg Neurol 1998;50:264 –71.

6.38 mm3 and 12,4 6 0.41%). Tizanidine is not effective if used just after reperfusion or later.

BACKGROUND

This study shows that Tizanidine pretreatment before the ischemic insult and the administration of the drug within the 2 hours after ischemia reduces ischemic damage significantly. Therefore, this drug can be used as a protective and therapeutic agent in ischemic diseases. © 1998 by Elsevier Science Inc.

Focal cerebral ischemia secondary to cerebral vessel occlusion is still an important cause of mortality and morbidity. Excitatory neurotransmitters are gathered in the extracellular space during ischemia and initiate or stimulate a series of pathophysiological biochemical processes and consequently lead to neuronal death. Tizanidine (Sandoz compound DS 103–282, 5-chloro-4,2 (2-imidazolin-2-yl-amino)-2,1,3-benzothiazol hydrochloride) is a selective a 2 adrenoreceptor agonist which shows its effect by stimulating presynaptic a 2 adrenoreceptors in central ASPergic and GLUergic system by inhibiting aspartic acid and glutamic acid release. In this study, the effect of Tizanidine on reversible focal cerebral ischemia was evaluated. METHODS

Cerebral blood flow to the left hemisphere of adult Sprague-Dawley rats (n 5 48) was temporarily interrupted by middle cerebral artery and bilateral common carotid artery occlusion for 3 hours in eight rats of each group. Tizanidine was given to each group of rats intraperitoneally before the ischemic insult, 2 hours after ischemia, right after the reperfusion, 2 h after reperfusion, and 4 hours after reperfusion; the animals survived for 24 hours after the reperfusion. After killing and triphenyltetrasoliumchloride staining of brain slices, infarction volumes and ratios of the brains were calculated and the results were compared with those of the control group. RESULTS

Infarction volumes and infarction ratios of the Tizanidine group 1/2 hours before ischemia (143.7 6 6.34 mm3 and 10.1 6 0.43%) and the Tizanidine group 2 hours after ischemia (145.6 6 6.32 mm3 and 10.3 6 0.43%) were found to be significantly lower in favor of the Tizanidine groups when compared with those of the control group (173.9 6

Address reprint requests to: Dr. M. Zafer Berkman, Halaskargazi Cad. Mimler Apt No. 337 Kat 4, S¸is¸li, Istanbul, Turkey. Received April 18, 1997; accepted Sept. 24, 1997. 0090-3019/98/$19.00 PII S0090-3019(97)00500-4

CONCLUSION

KEY WORDS

Focal cerebral ischemia, middle cerebral artery, reperfusion, tizanidine.

lthough intensive studies have been performed recently to prevent neural cell death after cerebral ischemia, death after cerebral ischemia continues to be a problem of utmost importance and its treatment is still a debated subject [14,31,50]. Neural tissue damage after cerebral ischemia occurs as a result of an increase in the tissue concentration of excitatory neurotransmitters, free radicals, and oxidants, diminished energy, acidosis, and cellular Ca11 influx [12,14,31,32,49 –51,53]. Excitatory neurotransmitters necessary for neuronal transmission are gathered in the extracellular space during ischemia and initiate or stimulate a series of pathophysiological biochemical processes which result in increased Ca11 and Na1 influx into the cell, rapid cellular swelling, and consequently neuronal death [1,40 – 42]. Tizanidine (Sandoz compound DS 103–282, 5chloro-4,2(2-imidazolin-2-yl-amino)-2,1,3-benzothiazol hydrochloride), a selective a 2 adrenoreceptor agonist, shows its effect by stimulating presynaptic a 2 adrenoreceptors in the central ASPergic and GLUergic system, by inhibiting aspartic acid and

A

© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

Tizanidine’s Effect on Focal Cerebral Ischemia

glutamic acid release [6 –10,13–22]. The effect of Tizanidine on reversible focal cerebral ischemia has not yet been assessed. The aim of this study is to evaluate the protective and therapeutic effects of Tizanidine on reversible focal cerebral ischaemia.

Materials and Method This study was performed in the Cerebrovascular Laboratory in the Department of Neurosurgery, Marmara University, Faculty of Medicine. All animals received proper animal care in compliance with the guidelines of Marmara University Research Council’s criteria. Adult male Sprague-Dawley rats weighing 260 –310 g were anaesthetised with intraperitoneal injection of 100 mg/kg ketamine and 10 mg/kg xylazine. Femoral arteries and veins of rats were catheterized by PG 50 polyethylene catheters; the arteries were connected to a Grass polygraph (Model 7 F, Grass Instrument Co., Quincy, MA, USA) with the help of a Grass transducer, and arterial blood pressures were monitored during all the surgical procedures and before killing. Arterial blood gases were obtained just before the surgical procedures began, every hour during the surgical procedures, and before killing. (GemSTAT 4600 Blood Gas/Electrolyte monitor, Mallinckrodt, Ann Arbor, MI, USA). At the same time, blood glucose levels were measured by means of the samples taken from the femoral veins. Throughout this experimental study, rectal temperatures of the rats were measured and body temperatures were kept constant in the 36 6 0.5 range with the help of an electronic thermostat and heating pads (Hilenastat electronic thermostat and Hilenaplan heating pad, Hilena Biologische und Chemische Erzeugnisse GmbH, Bielefeld, Germany). Arterial oxygen saturations of the rats were continuously monitored by Protocol 106 (Protocol Systems, Inc., Beaverton, OR, USA) during all the surgical procedures and before killing. SURGICAL PROCEDURE All the surgical procedures on the rats were performed under a microscope (Karl Kaps, Typ Som 82, Germany). The three-vessel occlusion protocol was used for three hours in order to obtain reversible focal cerebral ischemia [11,60]. Both common carotid arteries (CCA) were exposed through a midline vertical excision. The left middle cerebral artery (MCA) was exposed using the technique described by Tamura et al [55]. A 3-mm-diameter craniotomy, 1 mm lateral and 3 mm anterior to the foramen ovale, was fashioned using a dental drill.

Surg Neurol 265 1998;50:264 –71

The dura was incised with a 26 GF PPD needle. The proximal segment of the MCA (where it crosses the olfactory tract) and the lenticulostriate arteries were exposed. The MCA was occluded proximal to the olfactory tract and distal to the lenticulostriate arteries with a microsurgical mini clip (Sundt AVM Micro Clip 1, Codman & Shurtleff, Inc., Randolph, USA). Both common carotid arteries were also occluded with Yas¸argil mini aneurysm clips (FE 680, closing force: 119 gms, blade length: 3.0 mm, Aesculap AG, Tutlingen, Germany) within 2 min. During MCA occlusion the cortical surface was washed with heated physiological saline at 36.5°C. To prevent thrombus formation, 100 m/kg heparin (Liquemine, 500 IU/cc, Roche) was given intravenously every 90 min. At the end of the 3 hours, recirculation was established by removing all clips, and confirmed under the microscope by the inspection of the MCA. After recirculation, sponge gel was placed at the craniectomy site, and both scalp and neck incisions were closed. STUDY PLAN CONTROL GROUP. Eight rats. Reversible focal cerebral ischemia and reperfusion was performed and physiological saline was administered intraperitoneally. TIZANIDINE ADMINISTRATION 1/2 HOURS BEFORE ISCHEMIA (TIZ I). Eight rats. Intraperitoneal

0.3 mg/kg Tizanidine treatment began 1/2 hours before ischemic injury. TIZANIDINE ADMINISTRATION 2 HOURS AFTER ISCHEMIA (TIZ II). Eight rats. Intraperitoneal 0.3

mg/kg Tizanidine treatment began 2 hours after the ischemia. TIZANIDINE ADMINISTRATION RIGHT AFTER THE REPERFUSION (TIZ III). Eight rats. Intraperi-

toneal 0.3 mg/kg Tizanidine treatment began right after the reperfusion. TIZANIDINE ADMINISTRATION 2 HOURS AFTER REPERFUSION (TIZ IV). Eight rats. Intraperitoneal

0.3 mg/kg Tizanidine treatment began 2 hours after the reperfusion. TIZANIDINE ADMINISTRATION 4 HOURS AFTER REPERFUSION (TIZ V). Eight rats. Intraperitoneal

0.3 mg/kg Tizanidine treatment began 4 hours after the reperfusion. MORPHOMETRIC ANALYSIS OF HISTOPATHOLOGICAL CHANGES Twenty-four hours after the reperfusion, rats were anesthetized by diethyl ether and decapitated. The brain was removed immediately and the integrity of the left MCAs established by light microscopy. Lu-

266 Surg Neurol 1998;50:264 –71

minal preservation in the left MCA and both CCAs was evaluated in two rats in each group. After confirmation of the reperfusion, the brain was rinsed in chilled physiological saline for 5 min and 1.5-mm thick brain slices were cut. The brain slices were then immersed in 2% triphenyltetrasoliumchloride (TTC) (St. Louis, MO USA) solution at 37°C for 20 min to delineate the area of infarction. Images of dyed brain sections were recorded on video by a CL 110 AE Camera and a PS 11 A Camera Drive Unit and by using a Video Blaster. These were loaded on to an IBM PS II computer. By using a visual analysis program to keep the error level minimal in volume measurements, the front and the back surfaces of the infarct areas and the total areas of each brain slice were measured and their means were taken to be multiplied with the slice thickness to obtain the total brain volume and the infarct volume of each brain. The cumulative figures that were obtained from the slices revealed the total supratentorial brain and infarction volumes. The ratio of the total infarct volume to the total supratentorial brain volume was calculated to provide standardisation and for accurate comparison of the results. STATISTICAL ANALYSIS All the results were obtained as means 6 SEM for each study group. The statistical analysis of intragroup differences for physiological parameters was performed by means of the multiple analysis of variance (MANOVA) test. The differences between the groups in terms of physiological parameters were determined by using the one-way analysis of variance (ANOVA) test. In assessing the significance of infarction volumes and infarction ratios between the experimental groups, the one-way ANOVA test followed by Dunnet’s Multiple Comparison test was used, and p , 0.05 was considered significant.

Results The physiological parameters of the 48 rats studied are shown in Table 1. Four of the rats that died and five rats that had PaO2 saturation of less than 90% during the ischemia period were excluded. There was no statistically significant difference in physiological parameters between these groups (ANOVA). In addition to these results, there was no significant difference observed between the groups (MANOVA). During the study, neocortical infarction developed in all groups of rats. Infarction volumes and infarction ratios were obtained; their means and SE are shown in Table 2. These measurements were 173.9 6 6.38 mm3 and 12.4 6 0.41% for the control

Berkman et al

group, 143.7 6 6.34 mm3 and 10.1 6 0.43% for the Tizanidine administration group 1/2 hours before ischemia, 145.6 6 6.32 mm3 and 10.3 6 0.43% for Tizanidine administration group 2 hours after ischemia, 164.1 6 6.75 mm3 and 11.8 6 0.45% for the Tizanidine administration group right after the reperfusion, 168.7 6 6.8 mm3 and 11.9 6 0.44% for the Tizanidine administration group 2 hours after reperfusion, and 171.2 6 6.18 mm3 and 12.0 6 0.34% for the Tizanidine administration group 4 hours after reperfusion (values mean 6 SEM). When compared with the control group, the differences in the infarction volumes and in the infarction ratios of the Tizanidine administration group 1/2 hours before ischemia and the Tizanidine administration group 2 hours after ischemia were significantly lower in favor of the Tizanidine groups (one-way ANOVA followed by Dunnett’s Multiple Comparison test, p , 0.05).

Discussion In cerebral ischemia, the role of excitatory amino acids in neural tissue damage is of great importance. Aspartic acid and glutamic acid, which are excitatory amino acids, create excitatory postsynaptic potential in the central nervous system neuronal cells and thus provide neural transmission [2,8,40]. In ischemia, two types of cellular damage can be seen as a result of EAA receptor activation: osmolitic damage and damage attributable to Ca11. By the activation of the kainat and the quiskalat receptors, Na1 with water and Cl2 are transported into the cells and cause osmotic damage; and also thoursough the NMDA receptor, the Ca11 influx into the cells causes more severe damage. This increase in intracellular Ca11 initiates a series of reactions which in turn leads to cellular functional impairment and cell death [9,39,43]. In experimental studies, it has been shown that ischemia can be prevented by receptor antagonists [37,58,59]. It has been shown that in ischemia there is always an important increase in the concentration of the excitatory amino acids in the extracellular space [9,17,37,58]. In these studies it has been observed that after the first 10 min of ischemia, aspartic and glutamic acid increased thoursee times; 30 min after ischemia, aspartic acid increased 23 times and glutamic acid increased 163 times. By means of microdialysis methods it has been established that in cases of ischemia and hypoglycemia glutamates increase 8 –9 times. Tizanidine (Sandoz compound DS 103–282,

Tizanidine’s Effect on Focal Cerebral Ischemia

1

Surg Neurol 267 1998;50:264 –71

Physiological Variables During Experimental Study

GROUPS

AND

SAMPLING TIME

Control group Before occlusion During occlusion 1 h after occlusion 2 h after occlusion 3 h after occlusion 24 h after reperfusion TIZ administration 1/2 h before ischemia Before occlusion During occlusion 1 h after occlusion 2 h after occlusion 3 h after occlusion 24 h after reperfusion TIZ administration 2 h after ischemia Before occlusion During occlusion 1 h after occlusion 2 h after occlusion 3 h after occlusion 24 h after reperfusion TIZ administration right after the reperfusion Before occlusion During occlusion 1 h after occlusion 2 h after occlusion 3 h after occlusion 24 h after reperfusion TIZ administration 2 h after reperfusion Before occlusion During occlusion 1 h after occlusion 2 h after occlusion 3 h after occlusion 24 h after reperfusion TIZ administration 4 h after reperfusion Before occlusion During occlusion 1 h after occlusion 2 h after occlusion 3 h after occlusion 24 h after reperfusion

MABP

PO2

PCO2

HCT

PH

GLUCOSE

TEMP

PULSE

118 6 8 115 6 7 118 6 4 120 6 6 116 6 8 106 6 6

97 6 3 97 6 1 98 6 2 97 6 2 98 6 3 98 6 1

43 6 5 44 6 1 42 6 3 42 6 2 43 6 2 42 6 2

42 6 2 42 6 1 42 6 1 41 6 2 42 6 1 42 6 1

7.38 6 0.01 7.38 6 0.01 7.39 6 0.01 7.38 6 0.02 7.39 6 0.02 7.38 6 0.02

117 6 7 115 6 6 120 6 5 123 6 6 124 6 7 126 6 9

36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1

410 6 20 390 6 25 409 6 18 410 6 16 408 6 18 410 6 20

117 6 5 115 6 4 115 6 5 116 6 5 110 6 5 110 6 6

97 6 3 95 6 1 97 6 2 98 6 3 97 6 1 96 6 2

43 6 2 43 6 1 43 6 2 44 6 1 42 6 3 42 6 2

42 6 2 42 6 2 41 6 1 41 6 2 42 6 1 41 6 1

7.38 6 0.03 7.38 6 0.02 7.38 6 0.02 7.39 6 0.01 7.38 6 0.03 7.38 6 0.01

118 6 6 119 6 7 125 6 6 128 6 3 125 6 6 120 6 5

36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1

420 6 15 400 6 22 401 6 18 399 6 14 402 6 19 410 6 17

116 6 5 115 6 6 114 6 4 112 6 8 111 6 5 105 6 6

97 6 3 97 6 2 96 6 3 96 6 3 97 6 1 96 6 4

42 6 3 43 6 2 43 6 1 41 6 2 43 6 3 42 6 2

43 6 2 42 6 1 43 6 2 42 6 2 43 6 1 43 6 1

7.37 6 0.01 7.38 6 0.02 7.39 6 0.01 7.38 6 0.01 7.38 6 0.02 7.38 6 0.02

116 6 9 114 6 89 120 6 6 125 6 7 128 6 8 130 6 6

36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1

419 6 15 391 6 20 399 6 20 400 6 18 402 6 21 403 6 18

117 6 6 114 6 6 118 6 4 114 6 5 110 6 8 106 6 6

97 6 1 96 6 2 97 6 2 98 6 2 98 6 1 97 6 2

42 6 3 42 6 2 42 6 1 42 6 2 42 6 2 42 6 3

42 6 2 42 6 2 42 6 1 43 6 2 42 6 2 41 6 2

7.40 6 0.01 7.40 6 0.02 7.40 6 0.02 7.39 6 0.01 7.39 6 0.02 7.40 6 0.01

116 6 8 114 6 6 118 6 4 117 6 6 116 6 7 117 6 5

36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1

399 6 20 380 6 18 398 6 18 396 6 16 400 6 18 411 6 19

116 6 6 114 6 6 112 6 4 118 6 8 110 6 5 105 6 8

98 6 2 97 6 3 98 6 1 99 6 3 98 6 2 99 6 2

43 6 3 42 6 2 42 6 3 43 6 2 42 6 1 42 6 2

43 6 2 42 6 2 42 6 2 43 6 2 42 6 1 43 6 2

7.38 6 0.02 7.38 6 0.01 7.39 6 0.02 7.38 6 0.01 7.39 6 0.01 7.38 6 0.02

115 6 110 113 6 10 120 6 9 127 6 10 128 6 9 127 6 8

36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1

419 6 19 391 6 20 398 6 20 398 6 19 399 6 21 400 6 17

115 6 4 116 6 5 113 6 4 112 6 5 108 6 6 109 6 6

98 6 2 98 6 2 97 6 3 98 6 2 96 6 2 98 6 1

42 6 2 42 6 1 41 6 2 41 6 2 42 6 2 42 6 2

42 6 1 43 6 2 43 6 1 43 6 2 42 6 1 42 6 2

7.38 6 0.01 7.38 6 0.01 7.38 6 0.02 7.38 6 0.02 7.39 6 0.01 7.38 6 0.01

36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1 36.5 6 0.1

395 6 20 385 6 24 394 6 25 396 6 21 394 6 23 395 6 20

118 6 7 115 6 8 120 6 9 122 6 7 128 6 7 1129 6 8

TIZ, Tizanidine treatment group; MCA, middle cerebral artery; CCA, common carotid artery; MABP, mean arterial blood pressure; Hct, hematocrit; Temp, temperature in °C (values are presented as mean 6 SEM).

5-chloro-4,2 (2-imidazolin-2-yl-amino)-2,1,3-benzothiazole hydrochloride), a selective a 2 adrenoreceptor agonist, shows its effect by stimulating the presynaptic a 2 adrenoreceptors in the central ASPergic and GLUergic system, and by inhibiting aspartic acid and glutamic acid release [19,20,22]. Tizanidine, an imidazolin derivative, is a centrally

acting muscle relaxant that has an effect and structure similar to those of clonidine [3,4,7,15,25,35,56]. In 1980 it was reported by Sayers et al [47] to be the only centrally acting drug with a myotonolytic effect. Tizanidine is quite effective in reorganizing the impaired motor control of spasticity and in decreasing the increased muscle tone and spasm. The an-

268 Surg Neurol 1998;50:264 –71

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Infarction Volumes and Ratios Obtained in Control and Experimental Study Groups

INFARCTION MODEL Control group TIZ, administration 1/2 h before ischemia TIZ, administration 2 h after ischemia TIZ, administration right after the reperfusion TIZ, administration 2 h after reperfusion TIZ, administration 4 h after reperfusion

VOLUME (MM3)

INFARCTION RATIO (%)

173.9 6 6.38 143.7 6 6.34*

12.4 6 0.41 10.1 6 0.43*

145.6 6 6.32*

10.3 6 0.43*

164.1 6 6.75

11.8 6 0.45

168.7 6 6.8

11.9 6 0.44

171.2 6 6.18

12.0 6 0.34

TIZ, Tizanidine treatment group; MCA, middle cerebral artery; CCA, common carotid artery. Data presented as mean 6 SEM [*, statistically significant (p , 0.05)].

tispasmotic effect of Tizanidine is much stronger than baclofen, diazepam, and chlorzoxason, and it is also tolerated better [7,10,26,35,48]. Tizanidine is a strong centrally acting antinociceptive drug. This effect of Tizanidine cannot be antagonized by naloxen, so that the endogenous opioid system does not play a role in this effect, and this effect can be antagonized by yohimbin. All these facts indicate that Tizanidine is a centrally acting drug [15,19,28,30]. It has been shown that the antinociceptive effect of Tizanidine is much stronger than that of morphine when used subcutaneously, and its oral intake is as effective as the subcutaneous application of morphine [15,28]. Mebeshima et al [29] demonstrated the increased effectiveness of Tizanidine in intracerebroventricular application. There are various studies in which the antinociceptive and antispasmotic effects of Tizanidine were investigated [3,4,7,15,21,23,24,30,38,45]. For instance, de Sarro et al [5] reported the anticonvulsive effect of Tizanidine in rodent and primate epilepsy models; Maeda et al [20] reported the inhibition of gastric ulcer formation caused by drug intake by decreasing gastric acid secretion in rats; and Kameyama et al [16] reported hypothermic and antiinflammatory effects in rats. Sato et al [44,46] reported sedation and change in the behavioral patterns of monkeys, but with no effect on cat, rabbit, and rat temperature; TA, or biliary excretion; Simbulan and Kumazava [52] reported bradycardia in cats and, at the beginning stages, pressor rather than depressor effect on blood pressure; Takayani and Konno [54] reported mydriatic effect and inhibition of spontaneous stomach and ileum

peristalsis in rabbits and rats; and Ono et al [36] and McCarthy et al [23] reported no changes in blood pressure in rats. When taken orally Tizanidine reaches its maximum effectiveness in 1–2 hours. In 3– 4 hours its effect vanishes. Plasma half-life is 2.7 1 0.06 hours [21]. Clinically, Tizanidine has been used for spasticity caused by multiple sclerosis, strokes, syringomyelia, hereditary spastic paraparesis, stiffman syndrome, myelopathia choursonica, painful back syndromes, and for trigeminal neuralgia [6,7,13,18,19,21,24,26,27, 33,56,57]. There is no data available in the literature to evaluate the effects of Tizanidine administered after ischemic damage. In our study, the effect of Tizanidine on a transient focal cerebral ischemia model in rats was studied morphologically. The tested hypothesis was that the inhibition of particularly presynaptic EAA release by Tizanidine would result in a decreased ratio of infarction as the increase in EAAs is one of the mechanisms responsible for neural damage in the early ischemic period. In our study, at different times after the initiation of ischemia, 0.3 mg/kg Tizanidine was used intraperitoneally in 40 rats divided into five groups of eight rats each. In the literature, 20 mg/kg perioral, 5 mg/kg intraperitoneal, and IV up to 1 mg/kg applications have been reported and it has also been mentioned that the drug can be tolerated up to 24 mg [13,16,44 – 46]. In our study, we did not observe changes in the physiological parameters such as fluctuations in the arterial pressure, hypothermia, or sedation as reported in the literature [16,34,44,52]. The side effects of Tizanidine in clinical application were sleep disorders, dryness of the mouth, dizziness, muscle weakness, and depression [26,47]. We observed that, compared with the control group, when Tizanidine was given just before ischemia statistically significant decreases in the infarction volume and ratio occurred, and that the infarction volume and ratio could also be decreased significantly when Tizanidine was given 2 hours after ischemia. Tizanidine is not effective when used just after the reperfusion or later. In conclusion, our study postulates that in transient focal cerebral ischemia, Tizanidine has a prophylactic and a therapeutic effect when used just before ischemia or within the first 2 hours. In the light of these findings, we believe that from now on this drug will have a place in clinical application in the treatment of stroke-risk patients.

Tizanidine’s Effect on Focal Cerebral Ischemia

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COMMENTARY

The paper by Berkman et al on the effectiveness of tizanidine for focal cerebral ischemia is an exciting new approach to drug investigation for clinically useful neuroprotective agents. For the present, glutamate antagonists and voltage-sensitive calcium channel antagonists have been thoroughly investigated in the clinic; however, none proved as useful as recombinant tissue plasminogen activator (tPA), the thoursombolytic. What makes the present report exciting is that tizanidine, which was effective during the ischemic attack, does not require a differential diagnosis between thoursombus or hemorrhage as tPA does. Thus, one could administer this type of agent in the ambulance. This early administration potential enhances the therapeutic window by allowing treatment to begin as soon as stroke is recognized. The sooner neuroprotective treatment is started, the better. Future experimental work with this agent will determine the duration of treatment to ensure maximum benefits. Tizanidine stimulates the alpha-2 adrenergic receptor to inhibit the release of the neurotransmitter glutamate. This same mechanism is used by the antihypertensive agent clonidine which inhibits the release of norepinephoursine at central synapses. The key to the success of developing drugs of this type results from a targeted action at the release of transmitter, whereas the development of receptor antagonists on the post-synaptic membrane may require the development of a host of drugs to inter-

Tizanidine’s Effect on Focal Cerebral Ischemia

fere with the actions of a host of individual receptor subtypes. Although the development of receptor subtype antagonists may confer tissue and brain region specificity, tizanidine-type inhibitors are here now! The results presented in this paper are extremely encouraging because tizanidine proved effective in reducing infarct volume when administered during the ischemic insult, and also because with additional investigations of this drug at different dosages and a variety of treatment times, it may prove to be effective at later times during the ischemic

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insult or after reperfusion. There is evidence that the processes of injury continue to proceed long after the initial insult. Thus, this article gives further insight into the understanding of focal ischemia and lays the groundwork for the development of drugs which can be administered to the patient as soon as stroke is recognized. Lawrence Isaac, Ph.D. Department of Pharmacology University of Illinois at Chicago Chicago, Illinois

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here is more to life than increasing its speed. —Mahatma Gandhi