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A novel dibenzoxazepine derivative (BY-1949) increases regional cerebral blood flow
European Journal of Pharmacology, 178 (1990) 255-258 Elsevier
255
EJP 20591 Short communication
A novel dibenzoxazepine derivative (BY-1949) increases regional cerebral blood flow M a k o t o Sugawa, T o h r u Koide, A k i r a K o h d a a n d M i c h i a k i T a k a t o Department of Pharmacology, Exploratory Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135, Komakado, Gotemba, Shizuoka 412, Japan
Received 15 January 1990, accepted 6 February 1990
The effects of BY-1949, a novel dibenzoxazepine derivative, on the regional cerebral blood flow were investigated in conscious cats. Oral administration of BY-1949 (10-50 mg/kg) significantly increased in a dose-related manner the regional cerebral blood flow in all brain regions examined. Vinpocetine (20 mg/kg p.p.) had similar effects that were shorter-lasted than those of BY-1949. From these results, it seems likely that amelioration by BY-1949 of cognitive impairment following cerebral ischemia/hypoxia or that occurs on ageing is at least partly explainable in terms of its effects on the cerebral circulation. BY-1949; Cerebral blood flow (regional); Cerebrovascular disease
1. Introduction The most important clinical conditions leading to neuronal cell death in the brain are those associated with cerebrovascular disease, stroke in particular, and with head trauma (Siesj/5, 1981). Obviously, the pathophysiology of such conditions is influenced by a variety of factors, both intrinsic and extrinsic (Koide et al., 1986). Among extrinsic factors, cerebral blood flow can be taken as an important determinant of the location as well as magnitude of the insult incurred. In this regard, the evidence which shows that the use of cerebral vasodilators to reduce behavioural impairment in animals as well as mental deterioration in patients with stroke (Bagne et al., 1986; Balesteri et al., 1987), could indicate pharmacological tactics for the management of cerebrovascular disease.
Correspondence to: T. Koide, Department of Pharmacology, Exploratory Research Laboratories, Chugal Pharmaceutical Co. Ltd., 1-135, Komakado, Gotemba, Shizuoka 412, Japan.
BY-1949, 3-methoxy-11-methyldibenz(b,f),(1, 4)oxazepine-8-carboxylic acid, has been shown to ameliorate the cognitive impairment following cerebral ischemia/hypoxia, and to improve the behavioural retardation associated with ageing (Ikeda et al., 1988). The cellular mechanisms involved in the effect of the compound, however, remain to be determined. In the present study, we therefore, did experiments to investigate whether BY-1949 affects the regional cerebral blood flow in conscious cats. Vinpocetine, which is known to be a cerebral vasodilator (Pfilosi and Szporny, 1976), was used as an active control compound.
2. Materials and methods 2.1. Surgical procedures
Adult cats of either sex weighing 2.0-5.4 kg were used in this study. Platinum electrodes were implanted, according to the stereotaxic atlas of Snider and Niemer (1961), into the posterior
0014-2999/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
256
pentobarbital anesthesia (33 m g / k g i.p.). Catheters were also inserted into the femoral artery for arterial blood pressure measurements and blood gas analyses.
~
2.2. Measurements of regional cerebral blood flow
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Three weeks after surgery, each cat was placed in a box (30 × 32 × 32 cm) and allowed to accomodate to the new environment. For the regional cerebral blood flow measurements, hydrogen at a flow rate of 1.5 m l / m i n was given to the animal and the actual value of regional cerebral blood flow was calculated using a computer system (Signal Processor 7T17, Sanei, Tokyo) as previously reported by us (Asano et al., 1984). Arterial P O 2 , PCO 2 and p H were maintained at 90-110 mm Hg, 25-30 mm Hg and 7.35-7.45, respectively.
I
Fig. 1. Schematic drawing depicting the sites where the electrodes were implanted. (A) Posterior sigmoid gyms; (B) posterior sylvian gyms; (C) middle ectosylvian gyms; (D) posterior suprasylvian gyms; (E) hippocampus; (F) amygdala.
sigmoidal (A), posterior sylvian (B), middle ectosylvian (C), posterior suprasylvian (D) gyms, hippocampus (E) and amygdala (F) (fig. 1) under (%)
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Time after administration (min.) Fig. 2. Percent changes in regional cerebral blood flow following oral BY-1949 or vinpocetine administration to conscious cats. Each drug or vehicle (gum arabic) was administered at time zero. (©) Vehicle (n = 9); (e) BY-1949 (10 mg/kg) (n = 9); (A) BY-1949 (20 mg/kg) (n = 9); (11) BY-1949 (50 mg/kg) (n = 10); (zx) vinpocetine (20 mg/kg) (n = 9). Each value represents the mean + S.E.M. (A), (B), (C), (D), (E) and (F) correspond to the brain regions shown in fig. 1. * P < 0.05, * * P < 0.01.
257
2.3. Statistical analysis The results were analysed using the paired t-test and P values less than 0.05 were considered to indicate significant differences.
3. Results Prior to drug administration, the regional cerebral blood flow was measured several times in all experimental groups to find whether slight fluctuations of the value could be detected. The actual regional cerebral blood flow values thus obtained for each brain region were as follows: (A) 69.7 +_ 1.5 (n = 8); (B) 63.0 +_ 3.5 (n = 9); (C) 69.0+_2.5 ( n = 1 0 ) ; (D) 7 2 . 2 + 3 . 0 ( n = 1 0 ) ; (E) 68.3 _+ 4.4 (n = 7); (F) 57.2 _+ 2.4 (n = 9); (G) 59.7 _+ 4.8 (n = 6) (ml/100 g per min, mean _+ S.E.M. in each case). Oral administration of BY-1949 (10, 20 and 50 m g / k g ) significantly increased the regional cerebral blood flow in all brain regions examined in a dose-dependent manner, with the increase persisting for at least up to 60 min after drug administration (fig. 2). No apparent alterations in the systemic arterial blood pressure were observed throughout the experimental period (data not shown). An increased regional cerebral blood flow was also obtained in the case of vinpocetine (20 m g / k g p.c.), although its duration was shown to be shorter than with BY-1949.
4. Discussion The major finding from the present study was that a novel dibenzoxazepine derivative, BY-1949, virtually increased regional cerebral blood flow in conscious animals to the same extent as did vinpocetine. Summarizing the pharmacological data so far obtained, BY-1949 manifests beneficial effects on cognitive impairment during ageing and attenuates the derangements of brain energy metabolism following cerebral ischemia/hypoxia (Ikeda et al., 1988). From these data, in conjunction with the present results, it seems plausible
that the pharmacotherapeutic effects of BY-1949 are at least partly explainable by an increase in cerebral blood flow (SiesjO, 1981). Since increases in regional cerebral blood flow of the same magnitude as with vinpocetine were obtained with BY1949, the cerebrovascular effects of vinpocetine deserve consideration. Reports in the literature reveal that vinpocetine increases cerebral blood flow (Szmolenszky and Torok, 1976) and reduces behavioural deficits following ischemia/hypoxia in experimental animals (DeNoble et al., 1986; King, 1987), which can be taken as a pharmacological profile similar to that obtained with BY-1949. Moreover, it has recently been shown that vinpocetine alleviates symptomatic signs following stroke (Balestreri et al., 1987). Taken together, these data seem to be of particular importance since they offer the possibility that BY-1949 ameliorates cerebrovascular dysfunction in the clinical setting. Although the precise mechanisms of the vasodilatation caused by BY-1949 are still being evaluated in our laboratory, we do not believe, based on the evidence to date, that these effects are secondary to an increase in neural activity since no significant changes of the electroencephalogram were observed following oral administration of BY-1949 (Ikeda et al., 1988).
Acknowledgements The authors are deeply indebted to Professor Bo K. Siesj~, Laboratory for Experimental Brain Research, Lund University, Sweden, for giving us invaluable suggestions regarding this manuscript.
References Asano, T., H. Johshita, T. Koide and K. Takakura, 1984, Amelioration of ischaemic cerebral oedema by a free radical scavenger, AVS: 1,2-bis (nicotinamido)-propane. An experimental study using a regional ischemia model in cats, Neurol. Res. 6, 163. Bagne, C.A., N. Pomara, T. Crook and S. Gershon, 1986, Alzheimer's disease: strategies for treatment and research, in: Treatment Development Strategies For Alzheimer's Disease, eds. T. Crook, R.T. Bartus, S. Ferris and S. Gershon (Mark Powley Association, Inc., New York) p. 585.
258 Balestreri, R., L. Fontana and F. Astengo, 1987, A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction, J. Am. Geriat. 35, 425. DeNoble, V.J., S.J. Repetti, L.W. Gelpke, L.M. Wood and K.L. Keim, 1986, Vinpocetine: nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a stepthrough passive avoidance response in rats, Pharmacol. Biochem. Behav. 24, 1123. Ikeda, Y., S. Tanabe and M. Takatoh, 1988, Effects of dibenzoxazepine analogue (BY-1949) on acquisition process of operant behaviour in aged rats, Psychopharmacology 96, 305. King, G.A., 1987, Protective effects of vinpocetine and structurally related drugs on the lethal consequences of hypoxia in mice, Arch. Int. Pharmacodyn. 286, 299.
Koide, T., T.W. Wielroch and B.K. Siesj6, 1986, Circulating catecholamines modulate ischemic brain damage, J. Cereb. Blood Flow Metab. 6, 559. Pfilosi, E. and L. Szporny, 1976, Effects of ethyl apovincaminate on the central nervous system, Arzneim. Forsch. (Drug Res.) 26, 1926. Siesj/3, B.K., 1981, Cell damage in the brain: A speculative synthesis, J. Cereb. Blood Flow Metab. 1, 155. Snider, R.S. and W.T. Niemer, 1961, A Stereotaxic Atlas of The Cat Brain (The University of Chicago Press, Chicago and London). Szmolenszky, T. and B. Torok, 1976, Effect of ethyl apovincaminate on cerebral, cardiac and renal flow rate in dogs in the course of administration, Arzneim. Forsch. (Drug Res.) 26, 1914.
255
EJP 20591 Short communication
A novel dibenzoxazepine derivative (BY-1949) increases regional cerebral blood flow M a k o t o Sugawa, T o h r u Koide, A k i r a K o h d a a n d M i c h i a k i T a k a t o Department of Pharmacology, Exploratory Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135, Komakado, Gotemba, Shizuoka 412, Japan
Received 15 January 1990, accepted 6 February 1990
The effects of BY-1949, a novel dibenzoxazepine derivative, on the regional cerebral blood flow were investigated in conscious cats. Oral administration of BY-1949 (10-50 mg/kg) significantly increased in a dose-related manner the regional cerebral blood flow in all brain regions examined. Vinpocetine (20 mg/kg p.p.) had similar effects that were shorter-lasted than those of BY-1949. From these results, it seems likely that amelioration by BY-1949 of cognitive impairment following cerebral ischemia/hypoxia or that occurs on ageing is at least partly explainable in terms of its effects on the cerebral circulation. BY-1949; Cerebral blood flow (regional); Cerebrovascular disease
1. Introduction The most important clinical conditions leading to neuronal cell death in the brain are those associated with cerebrovascular disease, stroke in particular, and with head trauma (Siesj/5, 1981). Obviously, the pathophysiology of such conditions is influenced by a variety of factors, both intrinsic and extrinsic (Koide et al., 1986). Among extrinsic factors, cerebral blood flow can be taken as an important determinant of the location as well as magnitude of the insult incurred. In this regard, the evidence which shows that the use of cerebral vasodilators to reduce behavioural impairment in animals as well as mental deterioration in patients with stroke (Bagne et al., 1986; Balesteri et al., 1987), could indicate pharmacological tactics for the management of cerebrovascular disease.
Correspondence to: T. Koide, Department of Pharmacology, Exploratory Research Laboratories, Chugal Pharmaceutical Co. Ltd., 1-135, Komakado, Gotemba, Shizuoka 412, Japan.
BY-1949, 3-methoxy-11-methyldibenz(b,f),(1, 4)oxazepine-8-carboxylic acid, has been shown to ameliorate the cognitive impairment following cerebral ischemia/hypoxia, and to improve the behavioural retardation associated with ageing (Ikeda et al., 1988). The cellular mechanisms involved in the effect of the compound, however, remain to be determined. In the present study, we therefore, did experiments to investigate whether BY-1949 affects the regional cerebral blood flow in conscious cats. Vinpocetine, which is known to be a cerebral vasodilator (Pfilosi and Szporny, 1976), was used as an active control compound.
2. Materials and methods 2.1. Surgical procedures
Adult cats of either sex weighing 2.0-5.4 kg were used in this study. Platinum electrodes were implanted, according to the stereotaxic atlas of Snider and Niemer (1961), into the posterior
0014-2999/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
256
pentobarbital anesthesia (33 m g / k g i.p.). Catheters were also inserted into the femoral artery for arterial blood pressure measurements and blood gas analyses.
~
2.2. Measurements of regional cerebral blood flow
(~)(
Fro
;
I
Three weeks after surgery, each cat was placed in a box (30 × 32 × 32 cm) and allowed to accomodate to the new environment. For the regional cerebral blood flow measurements, hydrogen at a flow rate of 1.5 m l / m i n was given to the animal and the actual value of regional cerebral blood flow was calculated using a computer system (Signal Processor 7T17, Sanei, Tokyo) as previously reported by us (Asano et al., 1984). Arterial P O 2 , PCO 2 and p H were maintained at 90-110 mm Hg, 25-30 mm Hg and 7.35-7.45, respectively.
I
Fig. 1. Schematic drawing depicting the sites where the electrodes were implanted. (A) Posterior sigmoid gyms; (B) posterior sylvian gyms; (C) middle ectosylvian gyms; (D) posterior suprasylvian gyms; (E) hippocampus; (F) amygdala.
sigmoidal (A), posterior sylvian (B), middle ectosylvian (C), posterior suprasylvian (D) gyms, hippocampus (E) and amygdala (F) (fig. 1) under (%)
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Time after administration (min.) Fig. 2. Percent changes in regional cerebral blood flow following oral BY-1949 or vinpocetine administration to conscious cats. Each drug or vehicle (gum arabic) was administered at time zero. (©) Vehicle (n = 9); (e) BY-1949 (10 mg/kg) (n = 9); (A) BY-1949 (20 mg/kg) (n = 9); (11) BY-1949 (50 mg/kg) (n = 10); (zx) vinpocetine (20 mg/kg) (n = 9). Each value represents the mean + S.E.M. (A), (B), (C), (D), (E) and (F) correspond to the brain regions shown in fig. 1. * P < 0.05, * * P < 0.01.
257
2.3. Statistical analysis The results were analysed using the paired t-test and P values less than 0.05 were considered to indicate significant differences.
3. Results Prior to drug administration, the regional cerebral blood flow was measured several times in all experimental groups to find whether slight fluctuations of the value could be detected. The actual regional cerebral blood flow values thus obtained for each brain region were as follows: (A) 69.7 +_ 1.5 (n = 8); (B) 63.0 +_ 3.5 (n = 9); (C) 69.0+_2.5 ( n = 1 0 ) ; (D) 7 2 . 2 + 3 . 0 ( n = 1 0 ) ; (E) 68.3 _+ 4.4 (n = 7); (F) 57.2 _+ 2.4 (n = 9); (G) 59.7 _+ 4.8 (n = 6) (ml/100 g per min, mean _+ S.E.M. in each case). Oral administration of BY-1949 (10, 20 and 50 m g / k g ) significantly increased the regional cerebral blood flow in all brain regions examined in a dose-dependent manner, with the increase persisting for at least up to 60 min after drug administration (fig. 2). No apparent alterations in the systemic arterial blood pressure were observed throughout the experimental period (data not shown). An increased regional cerebral blood flow was also obtained in the case of vinpocetine (20 m g / k g p.c.), although its duration was shown to be shorter than with BY-1949.
4. Discussion The major finding from the present study was that a novel dibenzoxazepine derivative, BY-1949, virtually increased regional cerebral blood flow in conscious animals to the same extent as did vinpocetine. Summarizing the pharmacological data so far obtained, BY-1949 manifests beneficial effects on cognitive impairment during ageing and attenuates the derangements of brain energy metabolism following cerebral ischemia/hypoxia (Ikeda et al., 1988). From these data, in conjunction with the present results, it seems plausible
that the pharmacotherapeutic effects of BY-1949 are at least partly explainable by an increase in cerebral blood flow (SiesjO, 1981). Since increases in regional cerebral blood flow of the same magnitude as with vinpocetine were obtained with BY1949, the cerebrovascular effects of vinpocetine deserve consideration. Reports in the literature reveal that vinpocetine increases cerebral blood flow (Szmolenszky and Torok, 1976) and reduces behavioural deficits following ischemia/hypoxia in experimental animals (DeNoble et al., 1986; King, 1987), which can be taken as a pharmacological profile similar to that obtained with BY-1949. Moreover, it has recently been shown that vinpocetine alleviates symptomatic signs following stroke (Balestreri et al., 1987). Taken together, these data seem to be of particular importance since they offer the possibility that BY-1949 ameliorates cerebrovascular dysfunction in the clinical setting. Although the precise mechanisms of the vasodilatation caused by BY-1949 are still being evaluated in our laboratory, we do not believe, based on the evidence to date, that these effects are secondary to an increase in neural activity since no significant changes of the electroencephalogram were observed following oral administration of BY-1949 (Ikeda et al., 1988).
Acknowledgements The authors are deeply indebted to Professor Bo K. Siesj~, Laboratory for Experimental Brain Research, Lund University, Sweden, for giving us invaluable suggestions regarding this manuscript.
References Asano, T., H. Johshita, T. Koide and K. Takakura, 1984, Amelioration of ischaemic cerebral oedema by a free radical scavenger, AVS: 1,2-bis (nicotinamido)-propane. An experimental study using a regional ischemia model in cats, Neurol. Res. 6, 163. Bagne, C.A., N. Pomara, T. Crook and S. Gershon, 1986, Alzheimer's disease: strategies for treatment and research, in: Treatment Development Strategies For Alzheimer's Disease, eds. T. Crook, R.T. Bartus, S. Ferris and S. Gershon (Mark Powley Association, Inc., New York) p. 585.
258 Balestreri, R., L. Fontana and F. Astengo, 1987, A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction, J. Am. Geriat. 35, 425. DeNoble, V.J., S.J. Repetti, L.W. Gelpke, L.M. Wood and K.L. Keim, 1986, Vinpocetine: nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a stepthrough passive avoidance response in rats, Pharmacol. Biochem. Behav. 24, 1123. Ikeda, Y., S. Tanabe and M. Takatoh, 1988, Effects of dibenzoxazepine analogue (BY-1949) on acquisition process of operant behaviour in aged rats, Psychopharmacology 96, 305. King, G.A., 1987, Protective effects of vinpocetine and structurally related drugs on the lethal consequences of hypoxia in mice, Arch. Int. Pharmacodyn. 286, 299.
Koide, T., T.W. Wielroch and B.K. Siesj6, 1986, Circulating catecholamines modulate ischemic brain damage, J. Cereb. Blood Flow Metab. 6, 559. Pfilosi, E. and L. Szporny, 1976, Effects of ethyl apovincaminate on the central nervous system, Arzneim. Forsch. (Drug Res.) 26, 1926. Siesj/3, B.K., 1981, Cell damage in the brain: A speculative synthesis, J. Cereb. Blood Flow Metab. 1, 155. Snider, R.S. and W.T. Niemer, 1961, A Stereotaxic Atlas of The Cat Brain (The University of Chicago Press, Chicago and London). Szmolenszky, T. and B. Torok, 1976, Effect of ethyl apovincaminate on cerebral, cardiac and renal flow rate in dogs in the course of administration, Arzneim. Forsch. (Drug Res.) 26, 1914.