Partial cloning of CYP2C23a genes and hepatic protein expression in eight representative avian species.

Large interspecies differences in avian xenobiotic metabolism have been revealed by microsome-based studies, but specific enzyme isoforms in different bird species have not yet been compared. We have previously shown that CYP2C23 genes are the most induced CYP isoforms in chicken liver. In this study, we collected partial CYP2C23a gene sequences from eight avian species (ostrich, blue-eared pheasant, snowy owl, great-horned owl, Chilean flamingo, peregrin falcon, Humboldt penguin, and black-crowned night heron) selected to cover the whole avian lineage: Paleognathae, Galloanserae, and Neoaves. Genetic analysis showed that CYP2C23 genes of Galloanserae species (chicken and blue-eared pheasant) had unique characteristics. We found some duplicated genes (CYP2C23a and CYP2C23b) and two missing amino acid residues in Galloanserae compared to the other two lineages. The genes have lower homology than in other avian lineages, which suggests Galloanserae-specific rapid evolutionary changes. These genetic features suggested that the Galloanserae are not the most representative avian species, considering that the Neoaves comprise more than 95% of birds. Moreover, we succeeded in synthesizing an antipeptide polyclonal antibody against the region of CYP2C23 protein conserved in avians. However, comparative quantitation of CYP2C23 proteins in livers from six species showed that expression levels of these proteins differed no more than fourfold. Further study is needed to clarify the function of avian CYP2C23 proteins.

Diffusion tensor tractography of the Meyer loop in cases of temporal lobe resection for temporal lobe epilepsy: correlation between postsurgical visual field defect and anterior limit of Meyer loop on tractography.

BACKGROUND AND PURPOSE: Visual field defects sometimes occur after temporal resection surgery. Our purpose was to evaluate the correlation between visual field defects caused by temporal lobe resection and the degree of resection of the Meyer loop, as assessed by diffusion tensor tractography. MATERIALS AND METHODS: We examined 14 patients who underwent temporal resection for temporal lobe epilepsy. We obtained presurgical tractographies and then measured the distance between the temporal tip and the anterior limit of the Meyer loop (T-M distance). The degree of resection of the Meyer loop was defined as the distance from the anterior limit of the Meyer loop to the posterior limit of the temporal lobe resection (M-R distance). This was calculated by subtracting the T-M distance from the measured distance between the temporal tip and the posterior limit of the resection (T-R distance). RESULTS: The mean T-M distance was 36.6 mm. The interindividual variation of the distance ranged from 30.0 to 43.2 mm. Although there was no statistically significant correlation between the extent of the visual field defect and the T-R distance, there was a statistically significant correlation between the degree of the visual field defect and the M-R distance. CONCLUSION: The range of interindividual variation for the position of the Meyer loop was rather large, indicating that this variation is the key factor in visual field defects after temporal lobectomy, and the visual field defect appears to be predicted by presurgical tractography. Evaluation of the Meyer loop through the use of tractography seems to be a feasible method, which can be used to predict the visual field defect after temporal lobe resection.

The use of ultrasonic bone curettes in spinal surgery.

OBJECT: The author describes a clinical applications, procedure, and efficacy of ultrasonic bone curette (UBC) (bone-removal bar) in spinal surgery. METHODS: From July 2003 to March 2005, we operated on 98 consecutive spinal disorders by using UBC, Sonopet UST-2001; Chiari type-1 malformation (6 cases), cervical disorders (64 cases), thoracic disorders (5 cases), and lumbar disorders (23 cases). The instrument was devoid of any spinning parts, and the risk of grabbing cotton pledgets and damaging normal tissue was thereby avoided. Support from assistants for irrigation and suction was not required. FINDINGS: In this series, there were no iatrogenically induced injuries for example, direct or heat damage to surrounding soft tissues, including nerves, vessels, spinal cord, and dura matter. Considering potential complications of mechanical injuries by ultrasonic technique, intermittent usage and cotton protection during use under an operating microscope are recommended. We found that the ultrasonic device is easy to handle; however, it is time consuming for removing a large amount of bone and ossified lesions. Therefore, we recommend the combined use of this method with standard drilling. CONCLUSIONS: This system appears to be versatile, safe, and efficient in spinal surgery and could be improved by the development of a better handpiece.

Platelets treated with ticlopidine are less reactive to unusually large von Willebrand factor multimers than are those treated with aspirin under high shear stress.

Much attention has recently been focused on the interaction between unusually large von Willebrand factor multimers (UL-VWFM) and platelets under high shear stress in pathological thrombus formation. The antiplatelet drugs acetylsalicylic acid (aspirin) and a thienopyridine derivative (ticlopidine) are commonly used to treat cerebral ischemia but exert different effects on high-shear-stress-induced platelet aggregation (H-SIPA) in the plasma. To examine the effects of these drugs in the absence of plasma factors, we studied H-SIPA using washed platelets (WPs) and purified UL-VWFM. WPs were prepared from the blood of 9 aspirin-treated and 11 ticlopidine-treated patients with cerebral ischemia, and H-SIPA in the presence of UL-VWFM was measured using a cone plate aggregometer. Plasma levels of VWF antigen with its multimer analysis, ristocetin cofactor and VWF-cleaving protease (ADAMTS13) activity were also measured. Forty-six healthy volunteers from 2 age groups, 20-40 years (n=20) and 41-60 years old (n=26), were also tested as controls. H-SIPA was significantly inhibited for ticlopidine-treated platelets, but it was observed to a lesser extent for aspirin-treated platelets. For both groups, no difference in the plasma levels of VWF antigen, ristocetin cofactor and ADAMTS13 activity was noted. All patients possessed UL-VWFM, and it was detected in healthy volunteers with increasing frequency with increasing age. Under plasma-free conditions, platelets from aspirin-treated patients exhibit marginal but significant inhibition of H-SIPA. Furthermore, the presence of UL-VWFM in the plasma of patients and normal volunteers is directly related to their age rather than being a consequence of underlying disease.

Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction.

BACKGROUND AND PURPOSE: Cerebral venous ischemia often induces severe brain edema. Vascular endothelial growth factor (VEGF), which induces angiogenesis, is also known as vascular permeability (VP) factor. The present study was undertaken to investigate whether the inhibition of VEGF could reduce brain edema formation and cerebral venous infarction (CVI) in a rat 2-vein occlusion (2-VO) model. METHODS: We used 2-VO model in which 2 adjacent cortical veins were photochemically occluded. Male Wistar rats (n=25) were divided into 2 groups: one group was treated with a VEGF antagonist (antagonist group, n=10) and the second group was treated with phosphate-buffered solution (PBS) (PBS group, n=15). VEGF antagonist or PBS was injected intraperitoneally immediately after 2-VO. The developing ischemic infarct was evaluated by magnetic resonance imaging (MRI) and histology 24 hours after occlusion. RESULTS: VEGF expression was observed in the cytoplasm of neurons exclusively in the area of vasogenic edema that was shown as a high-intensity area in the apparent diffusion coefficient of water map. Ischemic volumes calculated from each MR images, which are related to infarction and/or vasogenic edema, respectively, were significantly smaller in the antagonist group as compared with the PBS group (P<0.05) CONCLUSIONS: Our study is the first to provide evidence that the inhibition of VEGF attenuates VP and reduces CVI in the acute stage. Although VEGF is a significant angiogenesis factor, we concluded that the inhibition of VEGF might be a new therapy for both brain edema formation and CVI.

Clinical features of postoperative cerebral venous infarction.

There is a potential risk of sacrificing the cortical vein during neurosurgical operations, particularly in the interhemispheric or subtemporal approach. An impaired cortical vein might cause cerebral venous circulatory disturbances (CVCDs) resulting in venous infarction. In this article, we have reviewed the management and results of eight cases with symptomatic postoperative venous infarction. We have encountered eight cases with symptomatic postoperative venous infarction (0.3%) during the past 5 years. The series is composed of 3 males and 5 females, with ages that ranged from 43 to 76 years (mean age of 58.1 years), and consisted of five brain tumors, one cavernoma, one dural AVF, and one trigeminal neuralgia. Initial symptoms occurred intra-operatively in two, on 0 day after the operation in one, 1 day in three, 3 days in one, and 4 days in one case. The symptoms were intra-operative brain edema in two cases, disorientation in one, cerebellar signs in one, hemiparesis in one, aphasia in two, and headache in one case. Two cases required surgical intervention. The results were a good outcome in 6 and a fair outcome in 2 cases. In conclusion, there are two types of postoperative venous infarction; severe onset (severe type) and gradual onset (mild type). The former needs immediate treatment from the intra-operative period onward, and the prevention of the ongoing venous thrombosis is essential in the latter.

Clinical features and management of brain arteriovenous malformations in elderly patients.

BACKGROUND: Brain arteriovenous malformations (AVMs) of the elderly have not received sufficient attention, given the increase in age of individuals in recent years. We therefore designed a retrospective study to clarify features of brain AVMs in this age group in comparison with their counterparts in the general population. METHODS: A retrospective study was performed, based on data for AVMs treated in Nara Medical University Hospital and affiliated hospitals over the past 13 years. The series included all cases of brain AVMs, except for pure dural AVMs, diagnosed from June 1989 to June 2003. A total of 175 patients were diagnosed as having an AVM during this period, including 32 patients more than 60 years old. Clinical features and effective treatment of brain AVMs in those over and under 60 were explored and outcome at 3 to 6 months after surgery was evaluated according to a modified neurological scale. FINDINGS: The most common mode of presentation was intracranial hemorrhage in both groups, and this was remarkable in the elderly. Epilepsy at presentation was less frequent in the elderly (P< 0.05). In the elderly group infratentorial lesions were encountered more frequently (P< 0.05). Good or excellent outcomes of surgery were accomplished in 82.6% of the non-elderly group, and in 69.6% of the elderly group. When restricted to the grades I or II of Spetzler and Martin (S & M) grading, postoperative neurological scores of both groups were significantly better than preoperative values (P < 0.01). In the grade III cases, the non-elderly demonstrated significant improvement after surgery (P <0.01), but the elderly did not. INTERPRETATION: Elderly patients with a brain AVM had clinical features of less frequent epileptic presentation and more frequent infratentorial lesions. It was suggested that surgery was acceptable in elderly patients with pallial AVMs of grade I and II. Surgery for grade III AVMs of the elderly remains to be clarified.

Syringomyelia caused by cervical spondylosis.

Syringomyelia is generally associated with Chiari type malformations, spinal tumors, or spinal trauma. Cervical spondylosis is only rarely involved. We here present a case of a 64-year-old woman with severe radicular pain in the right arm and the syringomyelic syndrome. Lateral radiographs of the cervical spine demonstrated spondylotic change at the C4/5 and C6/7 levels, and instability at C4/5. Dynamic magnetic resonance (MR) imaging revealed the spinal cord to be compressed at C5 and C6 with the body in extension, and the syrinx extended from C2 to the Th3 level on sagittal images. It was reduced remarkably after anterior decompression and stabilization at C4/5 and C6/7, and her symptoms also improved after surgery. We concluded that the syrinx in this case might have developed due to craniospinal pressure dissociation caused by intermittent spinal cord compression.

Observation of arterial and venous thrombus formation by scanning and transmission electron microscopy.

BACKGROUND: In order to examine the process of thrombosis formation in artery and vein, the reactions of the arterial and venous endothelial surfaces were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) in the photothrombosis model. MATERIALS AND METHODS: Thirty-nine rats were divided into the following 4 groups: 1) Sham group (n = 5) without illumination, 2) group A (n = 10) irradiated for 1 min, 3) group B (n = 10) irradiated for 5 min, 4) group C (n = 14) irradiated for 10 min at the level of the left common carotid artery and internal jugular vein. RESULTS: SEM provided no evidence of damage or adhesion of blood platelets to the endothelium of either the artery or vein in shams or group A animals. In group B, evidence of damage to endothelial cell membrane (e.g., plasmalemmal pits, crater-like structures associated with tears between endothelial cells, and decreased number of microvilli) was obtained in the arterial wall but not in the vein. In group C, there was extensive or widespread adhesion of blood platelets and other cells, tears between arterial endothelial cells, and a decrease in the number of microvilli in the artery but not in the vein (p < 0.05). CONCLUSIONS: Cell membrane injuries, tears between the endothelial cells, and endothelial detachment occur before adhesion of blood platelets and thrombus formation in the blood vessel occlusion model by photochemical reaction. These changes occur significantly earlier in the artery than in the vein.

Vasogenic edema and VEGF expression in a rat two-vein occlusion model.

Vasogenic edema plays an important etiologic role in the pathogenesis of cerebral venous circulation disturbances (CVCDs). Since vascular endothelial growth factor (VEGF) is a major mediator in angiogenesis and vascular permeability, including induction of vasogenic edema, the present study was undertaken to investigate whether it has any relevance to CVCDs. Male Wistar rats (n = 15) were used. Two adjacent cortical veins were occluded photochemically using rose bengal dye and fiberoptic illumination, with evaluation 24 hours thereafter by magnetic resonance imaging (MRI). Each brain was removed from the skull immediately after MRI and processed for hematoxylin-eosin staining (H&E staining) of sections for histopathology and comparison with MRI data. VEGF expression as demonstrated immunohistochemically appeared to coincide with vasogenic edema, diagnosed as high intensity areas on apparent diffusion coefficient of water (ADCw) maps. On the basis of these data, we conclude that VEGF is related to formation of vasogenic edema in the acute stage of CVCD.

Comparison of the effects of sevoflurane and propofol on cooling and rewarming during deliberate mild hypothermia for neurosurgery.

BACKGROUND: Because the time available for cooling and rewarming during deliberate mild hypothermia is limited, studies of the rate of the cooling and rewarming are useful. The decrease in core hypothermia caused by heat redistribution depends on the anaesthetic agent used. We therefore investigated possible differences between sevoflurane and propofol on the decrease and recovery of core temperature during deliberate mild hypothermia for neurosurgery. METHODS: After institutional approval and informed consent, 26 patients were assigned randomly to maintenance of anaesthesia with propofol or sevoflurane. Patients in the propofol group (n=13) received propofol induction followed by a continuous infusion of propofol 3-5 mg kg(-1) h(-1). Patients in the sevoflurane group (n=13) received propofol induction followed by sevoflurane 1-2%. Nitrous oxide and fentanyl were also used for anaesthetic maintenance. After induction of anaesthesia, patients were cooled and tympanic membrane temperature was maintained at 34.5 degrees C. After surgery, patients were actively rewarmed. RESULTS: There was no difference in the rate of decrease and recovery of core temperature between the groups. There was also no difference in skin surface temperature gradient (forearm to fingertip), heart rate and mean arterial blood pressure between the groups. CONCLUSIONS: Sevoflurane-based anaesthesia did not affect cooling and rewarming for deliberate mild hypothermia compared with propofol-based anaesthesia.

Effect of carotid endarterectomy on the ophthalmic artery.

BACKGROUND: To evaluate the effect of carotid endarterectomy on ophthalmic artery flow direction and peak systolic flow velocity, the authors examined the ophthalmic artery on 32 patients who had undergone carotid endarterectomy. METHODS: The 32 patients had more than 70% stenosis of the internal carotid artery at its origin on angiography. The ophthalmic artery ipsilateral to the carotid endarterectomy was evaluated by the ophthalmic artery color Doppler flow imaging before surgery and then at one week, one month, and three months after surgery. FINDINGS: (1) Before carotid endarterectomy: eight patients showed reversed ophthalmic artery direction. In the other 24 patients with antegrade ophthalmic artery flow direction, the average peak systolic flow velocity was 0.17+/-0.10 m/sec. (2) At one week after carotid endarterectomy: The reversed ophthalmic artery flow direction was resolved in each patient. The average peak systolic flow velocity in the patients with preoperative antegrade flow rose significantly to 0.28+/-0.10 m/sec (p<0.05). (3) At one month and three months after carotid endarterectomy: All patients showed the antegrade ophthalmic artery flow direction. The average peak systolic flow velocities showed no significant change compared to the value at one week after carotid endarterectomy. (4) During the followed up period, there was no patient showing worsening or recurrence of clinical symptoms including the visual symptoms. INTERPRETATION: Carotid endarterectomy brought about the correction of the reversed flow and an increase in the peak systolic flow velocity of the ipsilateral ophthalmic artery immediately after surgery.

Structure-function analysis of CYP27B1 and CYP27A1. Studies on mutants from patients with vitamin D-dependent rickets type I (VDDR-I) and cerebrotendinous xanthomatosis (CTX).

We have determined eight types of missense mutants of CYP27B1 from Japanese vitamin D-dependent rickets type I (VDDR-I) patients [Kitanaka, S., Takeyama, K., Murayama, A., Sato, T., Okumura, K., Nogami, M., Hasegawa, Y., Niimi, H., Yanagisawa, J., Tanaka, T. & Kato, S. (1998) New England J. Med., 338, 653-661 and Kitanaka, S., Murayama, A., Sakaki, T., Inouye, K., Seino, Y., Fukumoto, S., Shima, M., Yukizane, S., Takayanagi, M., Niimi, H., Takeyama, K. & Kato, S. (1999) J. Clin. Endocrine Metab., 84, 4111-4117]. None of the CYP27B1 mutants showed 1alpha-hydroxylase activity towards 25-hydroxyvitamin D3. Thus, it was assumed that the mutated amino-acid residues play important roles in the 1alpha-hydroxylase activity, such as substrate binding, activation of molecular oxygen, interaction with adrenodoxin, and folding of the cytochrome P450 structure. To examine our hypothesis, we generated various mutants of CYP27B1 and studied their enzymatic properties. In addition, the corresponding mutations were introduced to CYP27A1, which belongs to the same family as CYP27B1. As CYP27A1 showed much higher expression level than CYP27B1 in Escherichia coli, further analysis including heme-binding and substrate-binding was performed with CYP27A1 in place of CYP27B1. Western blot analysis, spectral analysis including reduced CO-difference spectra and substrate-induced difference spectra, and enzymatic analysis of the mutant CYP27A1 gave information on the structure-function relationships of both CYP27A1 and CYP27B1. Although the sequence alignment suggested that Arg107, Gly125, and Pro497 of CYP27B1 might be involved in substrate binding, the experimental data strongly suggested that mutations of these amino-acid residues destroyed the tertiary structure of the substrate-heme pocket. It was also suggested that Arg389 and Arg453 of CYP27B1 were involved in heme-propionate binding, and Asp164 stabilized the four-helix bundle consisting of D, E, I and J helices, possibly by forming a salt bridge. Thr321 was found to be responsible for the activation of molecular oxygen.

Enzymatic studies on the key enzymes of vitamin D metabolism; 1 alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24).

The key enzymes of vitamin D3 metabolism, renal 25-hydroxyvitamin D3 1 alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24) were expressed in Escherichia coli, and their enzymatic properties were revealed. As expected, mouse CYP27B1 and human CYP27B1 showed the 1 alpha-hydroxylation of 25-hydroxyvitamin D3 with the Michaelis constant, Km, value of 2.7 microM. Unexpectedly, both mouse CYP27B1 and human CYP27B1 showed greater Vmax/Km values toward 24,25-dihydroxyvitamin D3 than 25-hydroxyvitamin D3, suggesting that 24, 25-dihydroxyvitamin D3 is a better substrate than 25-hydroxyvitamin D3 for both CYP27B1. Enzymatic studies on substrate specificity of CYP27B1 revealed that 25-hydroxyl group of vitamin D3 was essential for the 1 alpha-hydroxylase activity, and 24-hydroxyl group enhanced the activity, but, 23-hydroxyl group greatly reduced the activity. On rat CYP24, it was demonstrated that CYP24 catalyzed four-step monooxygenation towards 25-hydroxyvitamin D3. Furthermore, in vivo and in vitro metabolic studies on 1 alpha,25-dihydroxyvitamin D3 clearly indicated that CYP24 catalyzed six-step monooxygenation to convert 1 alpha,25-dihydroxyvitamin D3 into calcitroic acid which is known as a final metabolite of 1 alpha,25-dihydroxyvitamin D3 for excretion in bile. These results strongly suggest that CYP24 is highly responsible for the metabolism of both 25-hydroxyvitamin D3 and 1 alpha,25-dihydroxyvitamin D3. In addition, we have succeeded in the construction of mitochondrial P450 electron transport chain consisting of ADR, ADX and each of CYP27B1 and CYP24 in E. coli cells. The coexpression system with CYP27B1 might be useful as a bioreactor to produce 1 alpha,25-dihydroxyvitamin D3. In contrast, the coexpression system with CYP24 would be applied to metabolic studies of vitamin D analogs used as drugs.

Intermittent isometric exposure prevents brain retraction injury under venous circulatory impairment.

It is recognized that surgical obliteration of the cerebral veins by additional brain compression using retractors is dangerous. However, there is a lack of satisfactory management of this problem. We investigated whether intermittent brain compression can reduce brain injury from cerebral venous circulation disturbances (CVCDs). In Wistar rats (n = 25), a solitary cortical vein was occluded photochemically. The brain surface was compressed by a spring balance and constant compression at 30 mmHg was carried out for 60 min. Intermittent procedure compression protocols included four 15 min compressions at 5 min intervals, intermittent isometric exposure (IM), and intermittent isotonic exposure (IT). Local cerebral blood flow (ICBF) in the compressed area was measured together by laser-Doppler (LD) with the degree of brain compression. After 24 h, the brains were examined histologically. The animals were divided into the following five groups (each n = 5): 1, a sham operated control; 2, cortical vein occlusion (VO); 3, VO + continuous brain compression (CC); 4, VO + IM; and 5, VO + IT. The ICBF decreased significantly during the compression; however, recovery after the series of compressions was observed only in the VO + IM group, not in the VO + CC and the VO + IT groups (p < 0.05). The depth of the brain surface increased stepwise in the VO + IT group compared with the VO + IM group (p < 0.01). The resulting tissue damage was significantly larger in the VO + CC and VO + IT groups than in the vein occlusion group (p < 0.05), but not in the VO + IM group. The results of the present study suggest that intermittent isometric exposure under CVCDs could decrease brain retraction injury during neurosurgical operations and be more beneficial than continuous compression, providing that the compression pressure declines as the process advances.

Radiosurgery-induced brain tumor. Case report.

The authors describe a case of glioblastoma multiforme (GBM) associated with previous gamma knife radiosurgery for a cerebral arteriovenous malformation (AVM). A 14-year-old boy had undergone radiosurgery for an AVM, which was performed using a 201-source 60Co gamma knife system at another institution. The maximum and margin radiation doses used in the procedure were 40 and 20 Gy, respectively. One year after radiosurgery, the patient noticed onset of mild left hemiparesis due to radiation necrosis. Six and one-half years after radiosurgery, at the age of 20 years, the patient experienced an attack of generalized tonic-clonic seizure. Magnetic resonance (MR) imaging revealed the existence of a brain tumor in the right parietal lobe. The patient underwent an operation and the histological diagnosis of the lesion was GBM. Ten months following the operation, that is, 99 months postradiosurgery, this patient died. To the best of the authors' knowledge, this is the first reported case of a neoplasm induced by radiosurgery for an AVM and the second case in which it occurred following radiosurgery for intracranial disease.

[A case of spontaneous subarachnoid hematoma of the high cervical spine presenting as Brown-Séquard's syndrome].

Spinal subarachnoid hematoma is a very rare event, occurring exclusively in the thoracic or lumbar region. We report the first recorded case of spontaneous subarachnoid hematoma in the high cervical spine presenting as Brown-Séquard's syndrome. A 57-year-old woman with no prior problems suddenly presented with Brown-Séquard's syndrome at the C1-2 disc space level following occiput neck pain. Her consciousness was clear and urinary retention was not observed. Lumbar puncture revealed no evidence of hemorrhage. Neuroradiological evaluation, including myelography, CT myelography, and MRI, demonstrated a defined hematoma in the cervical subarachnoid space at the C1-2 level. Angiographical study yielded negative findings. The patient's neurological state remained unchanged for the following 6 days. On the 7th day from the onset, a C1 and C2 laminectomy was performed. A defined clot was found after incising the intact dura matter and arachnoid membrane. This clot was easily aspirated except for a small part which was found attached to a pial vessel on the dorsal surface of the spinal cord. No underlying pathology other than coagulated blood was confirmed. Three months postoperatively, she had no neurological deficits. The clinical course of spontaneous spinal subarachnoid hematoma varies according to the rapidity and severity of hematoma formation. An immediate and precise diagnosis using multimodal neuroimagings is vital because decompressive surgery can dramatically ameliorate the neurological sequelae.

[Experimental study of pharmacological hypothermia: enhanced neuroprotective effect of a novel 5-HT 1 A agonist SUN N4057 by the pharmacological hypothermia].

PURPOSE: 5-hydroxytryptamine(5-HT) 1 A receptor agonists have a potentially marked neuroprotective reaction by both neuroprotective and hypothermic effects. We previously reported (1) the neuroprotective effect against the cerebral ischemia under normothermic condition, and (2) the hypothermic effect of the novel compound of 5-HT 1 A agonist, SUN N4057. The present investigation was designed to examine the enhancement of the neuroprotective effect by its pharmacological hypothermia. METHODS: In 24 anesthetized cats(body weight 1.9-4.6 kg), the left middle cerebral artery(MCA) occlusion was performed via the transorbital approach. Just after MCA occlusion, SUN N4057(6 micrograms/kg/min) was infused. Physiological parameters were measured continuously, and arterial blood gas was analyzed hourly for 6 hours and maintained within the normal ranges. Animals were randomly allocated to the following three groups: (1) ischemic controls infused with sterile saline(Group A, n = 8), (2) SUN N4057 under normothermic condition(Group B, n = 8), (3) SUN N4057 (Group C, n = 8). Then, brain coronal sections of 3 mm in thickness were stained with 1% triphenyltetrazolium chloride(TTC) solution, and hemispheric infarct volumes were calculated by using a computerized image analysis system. RESULTS: There were no significant differences in any physiological parameters among 3 groups. In Group C, brain temperature decreased significantly starting 1 hour after MCA occlusion and dropped by 2.1 +/- 0.7 degrees C 5 hours. Infarct volumes were 35.6 +/- 6.9% (Group A), 23.3 +/- 5.8% (Group B) and 12.3 +/- 11.3% (Group C), respectively. There were significant differences among three groups(p < 0.05). CONCLUSION: On the basis of these data, we conclude that SUN N4057 provides more effective neuroprotection by the combination of hypothermic and neuroprotective effects. Chemical hypothermia may lead to a new therapeutic approaches for treatment of brain ischemia.