The current status of reversal therapy in Japan for elderly patients with head injury treated with antithrombotic agents: A prospective multicenter observational study.

Background: Acute exacerbation of head injury in elderly patients due to use of antithrombotic agents has become a concern in countries with aging populations. Reversal agents are recommended for treatment, but its usage is unclear. Therefore, we conducted a prospective observational study in this patient population to monitor usage of reversal therapy. Methods: The subjects were 721 elderly patients aged ≥65 years old who were hospitalized in 15 centers from December 2019 to May 2021. Patients were divided into groups who did not receive antithrombotic agents (Group A), who received antithrombotic agents, but did not receive reversal therapy (Group B), and were treated with antithrombotic agents and reversal therapy (Group C). Age, gender, mechanism of injury, neurologic and imaging findings on admission, clinical course after admission and surgery, outcomes and complications were compared among these groups. Time from injury to reversal therapy was examined based on outcomes to investigate trends in the timing of administration of the reversal agent. Results: Acute exacerbation during the clinical course occurred in 9.8 %, 15.8 % and 31.0 % of cases in Groups A, B and C, respectively, and differed significantly among the groups. On head CT, the incidences of hematoma were 35.7 %, 36.5 % and 60.4 %, respectively, with this incidence being significantly higher in Group C; and the respective rates of craniotomy were 18.8 %, 14.0 % and 50.9 %, again with this rate being significantly higher in Group C. The good outcome and mortality rates were 57.1 %, 52.5 % and 35.8 %, and 14.5 %, 18.0 % and 24.5 %, respectively, and both were poorest in Group C. Times from injury to treatment with a reversal agent were significantly shorter in patients without compared to those with acute exacerbation (405.9 vs. 880.8 min) and in patients with favorable outcomes compared to those with unfavorable outcomes (261.9 vs. 543.4 min). Conclusion: Similarly to previous studies, the incidence of acute exacerbation was increased by use of antithrombotic agents. These results suggest that patients in Japan who require hematoma evacuation due to symptom exacerbation tend to be treated with reversal agents. Although it is difficult to assess the efficacy of reversal therapy from this study, earlier treatment with reversal agents before the occurrence of acute exacerbation may be useful to improve outcomes.

Machine Learning to Predict Three Types of Outcomes After Traumatic Brain Injury Using Data at Admission: A Multi-Center Study for Development and Validation.

The difficulty of accurately identifying patients who would benefit from promising treatments makes it challenging to prove the efficacy of novel treatments for traumatic brain injury (TBI). Although machine learning is being increasingly applied to this task, existing binary outcome prediction models are insufficient for the effective stratification of TBI patients. The aim of this study was to develop an accurate 3-class outcome prediction model to enable appropriate patient stratification. To this end, retrospective balanced data of 1200 blunt TBI patients admitted to six Japanese hospitals from January 2018 onwards (200 consecutive cases at each institution) were used for model training and validation. We incorporated 21 predictors obtained in the emergency department, including age, sex, six clinical findings, four laboratory parameters, eight computed tomography findings, and an emergency craniotomy. We developed two machine learning models (XGBoost and dense neural network) and logistic regression models to predict 3-class outcomes based on the Glasgow Outcome Scale-Extended (GOSE) at discharge. The prediction models were developed using a training dataset with n = 1000, and their prediction performances were evaluated over two validation rounds on a validation dataset (n = 80) and a test dataset (n = 120) using the bootstrap method. Of the 1200 patients in aggregate, the median patient age was 71 years, 199 (16.7%) exhibited severe TBI, and emergency craniotomy was performed on 104 patients (8.7%). The median length of stay was 13.0 days. The 3-class outcomes were good recovery/moderate disability for 709 patients (59.1%), severe disability/vegetative state in 416 patients (34.7%), and death in 75 patients (6.2%). XGBoost model performed well with 69.5% sensitivity, 82.5% accuracy, and an area under the receiver operating characteristic curve of 0.901 in the final validation. In terms of the receiver operating characteristic curve analysis, the XGBoost outperformed the neural network-based and logistic regression models slightly. In particular, XGBoost outperformed the logistic regression model significantly in predicting severe disability/vegetative state. Although each model predicted favorable outcomes accurately, they tended to miss the mortality prediction. The proposed machine learning model was demonstrated to be capable of accurate prediction of in-hospital outcomes following TBI, even with the three GOSE-based categories. As a result, it is expected to be more impactful in the development of appropriate patient stratification methods in future TBI studies than conventional binary prognostic models. Further, outcomes were predicted based on only clinical data obtained from the emergency department. However, developing a robust model with consistent performance in diverse scenarios remains challenging, and further efforts are needed to improve generalization performance.

The impact of hormonal dynamics and serum sodium fluctuations on symptomatic vasospasm after subarachnoid hemorrhage.

BACKGROUND: Symptomatic vasospasm (SVS) is a major cause of morbidity and mortality in aneurysmal subarachnoid hemorrhage (SAH), and serum sodium frequently decreases before SVS. Serum sodium changes might be regulated by sodium metabolism-related hormones. This multi-institutional prospective cohort study therefore investigated the measurement of sodium metabolism-related hormones to elucidate the pathophysiology of serum sodium changes in SAH. METHODS: SAH patients were treated with clipping or coiling from September 2017 to August 2020 at five hospitals. The laboratory data of 133 SAH patients were collected over 14 days and correlations between changes in serum sodium, sodium metabolism-related hormones (plasma adrenocorticotropic hormone (ACTH), serum cortisol, plasma arginine vasopressin (AVP)), and SVS were determined. Serum sodium concentrations were measured every day and serum sodium levels >135 mEq/L were maintained until day 14. RESULTS: Of the 133 patients, 18 developed SVS within 14 days of subarachnoid hemorrhage onset (SVS group) and 115 did not suffer from SVS (non-SVS group). Circulating AVP, ACTH, and cortisol concentrations were significantly higher on day 1 in the SVS group compared with the non-SVS group. Fluctuations in serum sodium in the SVS group were significantly higher than those in the non-SVS group. There were antiparallel fluctuations in serum sodium and potassium from days 2 to 14. CONCLUSIONS: Elevated levels of ACTH/cortisol and AVP on day 1 may be predictive markers for the occurrence of SVS. Multiple logistic regression analysis showed that serum sodium fluctuations were associated with SVS occurrence. Serum sodium fluctuations were associated with stress-related hormonal dynamics. (249 words).

[Brain Metastasis and Leptomeningeal Carcinomatosis after Surgery for Esophageal Cancer-A Case Report].

A 70-year-old man had undergone thoracoscopic esophagectomy following neoadjuvant chemotherapy for thoracic esophageal squamous cell carcinoma 3 years before presentation. He was undergoing whole-brain irradiation following surgery for a solitary brain metastatic tumor. The chief complaint was left leg pain during irradiation. FDG-PET/CT and MRI revealed metastases in bilateral cauda equina S1 nerve roots. Cerebrospinal fluid examination also revealed malignant cells. He received chemotherapy with 2 courses of 5-fluorouracil and cisplatin following 30 Gy of spinal irradiation. To control neurological symptoms, 4 courses of intrathecal chemotherapy with methotrexate, cytarabine, and betamethasone were performed. However, he gradually weakened and died 8 months after brain metastasis and 7 months after leptomeningeal carcinomatosis. The multidisciplinary treatment using irradiation and systemic and intrathecal chemotherapies could improve the survival of patients with leptomeningeal carcinomatosis of esophageal squamous cell carcinoma.

An Aneurysm at the Origin of a Duplicated Middle Cerebral Artery Treated by Stent-Assisted Coiling Using the "Wrapped-Candy" Low-Profile Visualized Intraluminal Support (LVIS) Technique: A Technical Case Report and Review of the Literature.

BACKGROUND: Aneurysms at the origin of a duplicated middle cerebral artery (DMCA) are quite rare. Here, we report a patient with such an aneurysm successfully treated endovascularly using our novel "wrapped-candy" low-profile visualized intraluminal support (LVIS) technique. CASE DESCRIPTION: A 44-year-old woman underwent endovascular treatment for an unruptured wide-necked aneurysm at the origin of a DMCA that incorporated the origin of the DMCA into its neck. Stent-assisted coiling was performed using our newly developed "wrapped-candy" LVIS technique. To protect the origin of the DMCA and increase the stent metal density at the neck, an LVIS blue 3.5-mm × 22-mm stent was deployed by pushing the delivery wire aggressively to transform the visible wire components of the LVIS into a shape like "wrapped candy," maximizing the strut compaction at the neck of the aneurysm. Subsequently, the aneurysm component was coiled using a jailed microcatheter. The final procedural angiography demonstrated almost complete aneurysm occlusion with DMCA preservation. CONCLUSIONS: Stent-assisted coiling can be a feasible treatment for an unruptured, usually wide-necked, aneurysm at the origin of a DMCA. The wrapped-candy LVIS technique may be useful in more challenging morphologies such as wide-necked aneurysms that incorporate the branch origin into the aneurysm neck.

Double Stent Retriever (SR) Technique: A Novel Mechanical Thrombectomy Technique to Facilitate the Device-Clot Interaction for Refractory Acute Cerebral Large Vessel Occlusions.

BACKGROUND: Mechanical thrombectomy has become the standard treatment for acute ischemic stroke caused by large vessel occlusion; however, refractory occlusions still occur despite various thrombectomy procedures. The double stent retriever (SR) technique, which employs 2 SRs simultaneously at the occlusion, can be useful for such refractory occlusions. METHODS: We described 2 cases of refractory acute cerebral occlusion despite the use of conventional thrombectomy procedures that were both treated with the double SR technique. To discuss the technical aspects of how this easy-to-perform technique facilitates the device-clot interaction, we also evaluated radiographic findings of the SR strut during the procedure. RESULTS: In both cases, conventional thrombectomy procedures, including an SR alone, an aspiration catheter alone, and combined use of the SR and aspiration catheter, failed to recanalize the occlusion. The double SR technique was then performed with the stent-in-stent method in 1 patient and the parallel stent method in 1 patient. One pass of this technique retrieved hard clots and successfully recanalized the refractory occlusion in both cases. Intraprocedural radiographic images of these cases showed that the degree of stent expansion improved after deployment of the second SR compared with the first SR. CONCLUSIONS: Our radiographic findings suggested that adding a second SR facilitates the device-clot interaction at the occlusion site. The double SR technique may be an easy-to-perform thrombectomy technique to improve clot-capturing ability for the management of refractory acute cerebral artery occlusions.

Transvenous embolization through the ipsilateral deep facial vein: A novel approach route for treatment of a cavernous sinus dural arteriovenous fistula.

The superior ophthalmic vein (SOV) approach through the facial vein is usually preferred for transvenous embolization of a cavernous sinus dural arteriovenous fistula (CS DAVF) when the ipsilateral inferior petrosal sinus is angiographically occluded. However, navigating the microcatheter can sometimes be difficult because of stenosis or tortuous angulation at the junction between the angular vein and SOV. We present a novel transvenous access route to treat a CS DAVF using the ipsilateral deep facial vein through the SOV to reach the cavernous sinus. A 66-year-old woman presented with left-sided chemosis, exophthalmos, and external ophthalmoplegia. Angiography showed a left CS DAVF associated with a dilated SOV and retrograde cortical venous reflux. A dilated drainage vein, which branched from the SOV, ran through the lateral aspect of the orbit and exited the orbit through the inferior orbital fissure. This vein connected with the ipsilateral deep facial vein draining into the facial and internal jugular veins. We performed transvenous embolization via the SOV approach through the deep facial vein and achieved complete obliteration, by placing 3 platinum coils, without complications. Ophthalmic veins may connect with the cavernous sinus and pterygoid plexus, passing through the superior and inferior orbital fissures, respectively. Our case suggests that the deep facial vein may provide access to the SOV through the inferior orbital fissure without passing the difficult tortuous angle between the angular vein and SOV.

Machine Learning to Predict In-Hospital Morbidity and Mortality after Traumatic Brain Injury.

Recently, successful predictions using machine learning (ML) algorithms have been reported in various fields. However, in traumatic brain injury (TBI) cohorts, few studies have examined modern ML algorithms. To develop a simple ML model for TBI outcome prediction, we conducted a performance comparison of nine algorithms: ridge regression, least absolute shrinkage and selection operator (LASSO) regression, random forest, gradient boosting, extra trees, decision tree, Gaussian naïve Bayes, multi-nomial naïve Bayes, and support vector machine. Fourteen feasible parameters were introduced in the ML models, including age, Glasgow Coma Scale (GCS), systolic blood pressure (SBP), abnormal pupillary response, major extracranial injury, computed tomography (CT) findings, and routinely collected laboratory values (glucose, C-reactive protein [CRP], and fibrin/fibrinogen degradation products [FDP]). Data from 232 patients with TBI were randomly divided into a training sample (80%) for hyperparameter tuning and validation sample (20%). The bootstrap method was used for validation. Random forest demonstrated the best performance for in-hospital poor outcome prediction and ridge regression for in-hospital mortality prediction: the mean statistical measures were 100% sensitivity, 72.3% specificity, 91.7% accuracy, and 0.895 area under the receiver operating characteristic curve (AUC); and 88.4% sensitivity, 88.2% specificity, 88.6% accuracy, and 0.875 AUC, respectively. Based on the feature selection method using the tree-based ensemble algorithm, age, Glasgow Coma Scale, fibrin/fibrinogen degradation products, and glucose were identified as the most important prognostic factors for poor outcome and mortality. Our results indicate the relatively good predictive performance of modern ML for TBI outcome. Further external validation is required for more heterogeneous samples to confirm our results.

[Clinical Features and Treatment Strategy of Vertebral Artery Injury Associated with Cervical Spine Trauma].

OBJECTIVE: Vertebral artery injury(VAI)associated with cervical spine trauma has the potential to cause catastrophic vertebrobasilar stroke. However, there are no well-defined treatment recommendations for VAI. The purpose of this study was to identify an effective treatment strategy for VAI following cervical spine trauma. METHODS: Ninety-seven patients with blunt cervical spine trauma were treated at Hyogo Prefectural Kakogawa Medical Center between January 2013 and September 2017. Of these patients, 49 underwent computed tomographic angiography or magnetic resonance angiography for evaluation of the vertebral artery. Eighteen patients(36.7%)had a diagnosis of VAI. We retrospectively analyzed the clinical features, treatment, and outcomes in these 18 patients. RESULTS: Seven patients(38.9%)had bilateral VAI, 16(88.9%)had cervical dislocation, and 2(11.1%)had transverse process fractures extending into the transverse foramen. Surgical reduction was performed in 14 patients. Five patients with either bilateral or unilateral occlusion underwent parent artery occlusion before reduction. There were no complications after this procedure. Two patients with bilateral VAI had a stroke before treatment. There were no infarctions in the distribution of the vertebrobasilar artery after intervention. The perioperative stroke rate was relatively good, and almost all Glasgow Outcome Scale scores were related to the degree of spinal cord injury. CONCLUSIONS: Aggressive screening for VAI is important in patients with cervical spine trauma in order to ensure adequate treatment. Although the treatment strategy described here could yield good results, it may require modification according to the needs of the individual patient.

[A Pediatric Case of Intractable Cerebrospinal Fluid Leakage after Implantation of an Intrathecal Baclofen Pump].

Intrathecal baclofen(ITB)infusion can offer a useful treatment for severe spasticity;however, numerous complications have been reported. We report a pediatric case in which intractable cerebrospinal fluid(CSF)leakage associated with several inconvenient symptoms arose after implantation of the ITB pump system. A 10-year-old girl with spastic quadriparesis and athetoid cerebral palsy underwent implantation of an ITB delivery system. After discharge, she presented with fluid collection surrounding the pump in the abdomen. The volume of fluid increased and was percutaneously aspirated every other week. However, conservative management failed to relieve fluid collection, which was suspected to be due to CSF leakage. She underwent additional purse-string suture of the point inserted catheter insertion in the back, epidural blood patch, and subfascial implantation of an anchor. However, none of these therapies proved effective. Progressive enlargement of the accumulated fluid was observed. Furthermore, symptoms of ITB withdrawal appeared. Lumbar-peritoneal shunting was performed, and the subcutaneous fluid collection was relieved postoperatively. The course after shunting was uneventful;hence, the dose of baclofen was stabilized. No recurrence of fluid collection was encountered for two years. Intractable CSF leakage was thought to be caused by wasting, occult hydrocephalus, and twisted movements. This case indicates that care is required in the management of CSF leakage after ITB pump implantation.

New technique of decompressive skinplasty with artificial dermis for severe brain swelling: technical note.

In cases of severe uncontrollable brain swelling, simple skin closure often increases intracranial pressure. This study examined the efficacy of a new technique of decompressive skinplasty to decrease intracranial pressure following decompressive craniectomy in cases of severe traumatic brain injury with uncontrollable brain swelling. In our technique, we use artificial dermis to avoid elevation of intracranial pressure. After performing decompressive craniectomy and duraplasty with artificial dura, decompressive skinplasty with artificial dermis was performed in 5 patients for whom simple skin closure caused the intracranial pressure to elevate under intracranial pressure monitoring. Artificial dermis was grafted onto the region to cover the skin defect and sutured to the skin with 4-0 nylon sutures. Two weeks after surgery, the silicone layer of the artificial dermis was removed and ointment treatment was continued until complete epithelialization was achieved. In all cases, decompressive skinplasty contributed dramatically to decreasing the intracranial pressure in patients with uncontrollable brain swelling. The technique of decompressive skinplasty with artificial dermis contributed to dramatically decreasing the intracranial pressure. More cases are required to investigate the indications for this technique.

Syringomyelia due to thoracic spinal stenosis with ossified ligamentum flavum--case report.

A 50-year-old male presented with back pain and numbness of the lower extremities persisting for 10 years. He had played volleyball for a long period until recently. He had no history of meningitis or traumatic injury. Magnetic resonance imaging revealed a syringomyelia located in the region from T8 to T9 without contrast enhancement or Chiari malformations. Computed tomography showed T9-10 spinal stenosis caused by the right enlarged ossified yellow ligament. Decompressive laminectomy was performed and the ossified ligament removed. Due to the finding of arachnoid thickening and adhesions during the intradural operation, shunting was also performed. Postoperatively, the neuroimaging and clinical findings improved. Syringomyelia is often associated with Chiari malformations, trauma, spinal tumor, hemorrhaging, and meningitis. We suggest that repeated minor mechanical damage caused by physical exercise in addition to long-standing compression of the spinal cord due to spinal spondylosis could induce severe arachnoid fibrotic change similar to adhesive arachnoiditis, which may be one of the main triggers of syringomyelia. Extradural decompressive surgery is considered to be the initial treatment for syringomyelia associated with spinal spondylosis.

Xanthogranuloma of the sellar region--case report.

A 55-year-old woman presented with a rare xanthogranuloma of the sellar region after complaining of severe headache and visual disturbance 3 months previously. Clinical examination showed she was alert with early signs of bitemporal hemianopsia. Endocrinological examination revealed hypopituitarism. Magnetic resonance imaging showed an intrasellar mass extending into the suprasellar region and compressing the optic chiasma, which appeared homogeneously hyperintense on T(1)-weighted images. Endonasal transsphenoidal resection of the tumor was performed. Histological examination disclosed granulomatous tissue with cholesterol clefts, hemosiderin deposits, fibrous tissues, and macrophages containing rich fat. The histological diagnosis was xanthogranuloma of the sellar region. Her visual symptoms recovered postoperatively although the hypopituitarism remained. Xanthogranuloma of the sellar region is rare, but must be considered in the differential diagnosis of tumors of the sellar region.

Solitary metastatic tumor within the optic chiasm--case report.

A 61-year-old female, previously treated for lung cancer, presented with a rare case of metastasis directly to the optic chiasm manifesting as visual deficits. Magnetic resonance imaging revealed a suprasellar mass similar to an optic glioma. At surgery, the optic chiasm appeared swollen with hypervascularity over the surface. The bilateral optic nerves and the pituitary stalk appeared normal. A small incision was made on the superior surface of the chiasm and biopsy specimens were taken. The histological diagnosis was adenocarcinoma, which was consistent with the primary lung cancer. She received whole brain irradiation, resulting in mild improvement of her vision. Suprasellar metastatic tumors to the pituitary gland, pituitary stalk, and hypothalamus are well documented, but solitary metastasis within the optic chiasm should be considered as one of several differential diagnoses of suprasellar tumors, in patients with or without a history of treated cancer.

Intradural facial nerve schwannoma: diagnostic and therapeutic problems.

OBJECTIVES: To define characteristics of intradural facial schwannoma (FS) and discuss management strategies. METHOD: Retrospective review of clinical charts. RESULTS: Six patients were diagnosed, based on surgical findings, as having intradural FS. None of the patients complained initially of facial weakness, but all showed severe disturbance of hearing function assessed on admission. FS was suspected in four of our six patients because of imaging findings or facial palsy caused by a small tumor. Total removal was performed in five cases followed by facial nerve reconstruction, and nearly total removal was performed in one case. Most patients recovered to Grade II or III palsy during the follow-up, and long-lasting palsy before surgery showed poor recovery. CONCLUSION: Imaging findings such as tumor extension to the middle fossa and clinical findings such as facial palsy caused by a small tumor strongly suggest a diagnosis of FS. Facial function can be restored satisfactorily for most patients after appropriate surgery.

[A case of amebic brain abscess].

Amebic brain abscess is a rare and usually fatal complication of Entamoeba histolytica infections. We successfully treated a patient with this infection accompanied by brain, liver and pulmonary abscesses. Treatment consisted of administration of metronidazole through a nasogastric tube, and drainage of the brain abscess. A 51-year-old male patient presented with a two-week history of fever, severe back pain, and chest pain. Liver and pulmonary abscesses were drained upon admission. Biopsy of the colon showed infection by Entamoeba histolytica. After oral administration of metronicazole, the patient became somnolent, and neurological examination showed left side weakness. CT scan and MRI of the brain disclosed an abnormal lesion in the right basal ganglia. He was then transferred to our department, where stereotactic aspiration with drainage of the brain abscess was performed. The abscess was filled with reddish purulent material. Treatment with metronidazole (1,200 mg daily) for 18 days resulted in almost complete resolution of the intracerebral lesion and survival of the patient without any neurological deficits. His general condition improved dramatically, and he was discharged from our hospital 2 months later. Only 14 cases with amebic brain abscess associated with Entamoeba histolytica infection who recovered after treatment have been reported. We suggest amebic brain abscess should be taken into consideration for patients with brain abscess with a history of dysenteric illness especially since early diagnosis and aggressive management is likely to result in a cure.

New technique for decompressive duraplasty using expanded polytetrafluoroethylene dura substitute--technical note.

A new technique for decompressive craniectomy with duraplasty was developed for cases in which brain swelling was present at dural closure. Expanded polytetrafluoroethylene (ePTFE) membrane is placed under the dura, covering the brain surface, without the use of sutures. The dura is then loosely sutured. The procedure was used in 13 patients. No leakage of cerebrospinal fluid into the epidural space or signs of infection were observed. Sutureless insertion of an ePTFE membrane at external decompression may increase the ease of duraplasty, decrease operating time, and avoid injury to the brain resulting from suturing the dura. The technique might be especially useful in emergency cases.

Presacral meningocele associated with hereditary sacral agenesis and treated surgically: evaluation in three members of the same family.

OBJECTIVE AND IMPORTANCE: Presacral meningocele in hereditary sacral agenesis is a complex and unusual spinal dysgenetic syndrome. Recognition of the syndromic triad, its natural history, and familial presentation has important practical applications for the management of this disease as well as its complications. CLINICAL PRESENTATION: This report concerns three patients in one family with Currarino syndrome. We detail its clinical presentation, operative management, and outcome and suggest management procedures based on reports in the literature and the results of our surgical techniques, which focus on cases with an "incomplete" triad. INTERVENTION: Three members of the same family, one adult and two children, underwent surgery through the posterior sacral approach tying off the communication between dural sac and anterior meningocele. The adult underwent a second surgical procedure in which a custom-designed surgical technique was used to resolve postoperative cerebrospinal fluid leakage. One of the children underwent an additional posterior sagittal anorectoplasty to remove a presacral teratoma. CONCLUSION: We report a rare occurrence of three familial cases of sacral agenesis accompanied by a presacral mass with various degrees of phenotypic expression and with male dominant transmission. Because of its rarity, the best surgical technique and timing remain an open question especially in cases with incomplete triad syndrome.

Adenosine triphosphate accelerates recovery from hypoxic/hypoglycemic perturbation of guinea pig hippocampal neurotransmission via a P(2) receptor.

The present study was designed to assess the effects of adenosine triphosphate (ATP) on hippocampal neurotransmissions under the normal and hypoxic/hypoglycemic conditions. ATP reversely depressed population spikes (PSs), which were monitored in the dentate gyrus of guinea pig hippocampal slices, in a dose-dependent manner at concentrations ranged from 0.1 micro M to 1 mM. A similar depression was obtained with the P(2) receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP), and the effect was inhibited by the P(2) receptor antagonists, suramin and PPADS. The inhibitory action of ATP or alpha,beta-MeATP was inhibited by the gamma-aminobutyric acid(A) (GABA(A)) receptor antagonist, bicuculline, but it was not affected by theophylline, a broad inhibitor of adenosine (P(1)) receptors, tetraethylammonium, a broad inhibitor of K(+) channels, or ecto-protein kinase inhibitors. ATP or alpha,beta-MeATP enhanced GABA release from guinea pig hippocampal slices, that was inhibited by deleting extracellular Ca(2+) or in the presence of tetrodotoxin, while ATP had no effect on GABA release from cultured rat hippocampal astrocytes or postsynaptic GABA-gated channel currents in cultured rat hippocampal neurons. Twenty-minutes deprivation of glucose and oxygen from extracellular solution abolished PSs, the amplitude recovering to about 30% of basal levels 50 min after returning to normal conditions. ATP or alpha,beta-MeATP accelerated the recovery after hypoxic/hypoglycemic insult (approximately 80% of basal levels). Adenosine diphosphate and adenosine monophosphate accelerated the recovery, but to a much lesser extent, and adenosine had no effect. The results of the present study thus suggest that ATP inhibits neuronal activity by enhancing neuronal GABA release via a P(2) receptor, perhaps a P2X receptor, thereby protecting against hypoxic/hypoglycemic perturbation of hippocampal neurotransmission.