DeCure's autonomous Cardio AI scientist is researching a drug-repurposing hypothesis for cerebral arterial disease — screening already-approved drugs against its 28-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCerebral arterial disease maps to a 28-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
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Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Structures already discussed alongside cerebral arterial disease in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Crystal structure of wild type LFA1 I domain — Isoflurane has a real, experimentally solved structure in complex with this target (PDB 3F78, 1.6 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet icfdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3F78 · 1.6 Å · ligand Isoflurane (ICF). Experimental structure, not a prediction.
What the evidence adds up to
In 174 cases of cerebral arterial insufficiency, arteriography showed that extracranial arterial lesions could account for the condition in about one third of patients. Surgical treatment was performed in 63 of those patients, and the results were evaluated based on restoration of circulation, clinical improvement, and survival. The abstract gives no numerical outcomes for these endpoints, no survival rates, and no response rates, so the actual benefit of surgery in this 1959 series cannot be quantified from the text.
A 2021 transcriptome study of cerebral arteriovenous malformation (AVM) nidus tissue identified 38 differentially expressed genes compared to controls: 35 upregulated and 3 downregulated. The key finding was upregulation of ALDH1A2, a rate-limiting enzyme in retinoic acid signalling, and of CYR61, a retinoic acid target gene that regulates angiogenesis. Astrocytes associated with the AVM nidus were abnormal, with increased GFAP and Vimentin expression, and CYR61 was also overexpressed in those abnormal astrocytes. The authors speculate that this deregulated retinoic acid signalling might trigger abnormal angiogenesis and AVM development, but no therapeutic intervention was tested.
A 2019 study compared endothelial cells from the intracranial basilar artery and the extracranial common carotid artery from the same 15 individuals post-mortem. RNA sequencing showed that intracranial artery endothelial cells have a distinct molecular signature, including an immune quiescent phenotype and differential expression of genes involved in inflammation, differentiation, adhesion, proliferation, permeability, and oxidative stress. Three genes — Desmoplakin (DSP), Hop Homeobox (HOPX), and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B) — were responsive to shear stress or hypoxia. The authors propose that these intracranial-specific endothelial genes may contribute to a protective phenotype that preserves cognitive function, but no drug or intervention was tested in this study.
What is still missing: no drug has been tested in any of these studies for cerebral arterial disease. The surgical series from 1959 lacks control-group comparison and modern statistical reporting. The molecular studies identify candidate pathways (retinoic acid signalling, endothelial protective genes) but have not moved to preclinical drug testing or patient stratification. Funding for translational work that connects these molecular leads to clinical trials in cerebral arterial disease remains absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Critical Care Medicine · 2012 · 82 citations
Inhalation versus endovenous sedation in subarachnoid hemorrhage patients
AbstractOBJECTIVE: Isoflurane is a volatile anesthetic that has a vasodilating effect on cerebral vessels producing a cerebral blood flow increase. Furthermore, it has been shown in animal studies that isoflurane, when used as a preconditioning agent, has neuroprotective properties, inducing tolerance to ischemia. However, it is not routinely used in neurointensive care because of the potential increase in intracranial pressure caused by the rise in cerebral blood flow. Nevertheless, subarachnoid hemorrhage patients who are at risk for vasospasm may benefit from an increase in cerebral blood flow. We measured regional cerebral blood flow during intravenous sedation with propofol and during sedation with isoflurane in patients with severe subarachnoid hemorrhage not having intracranial hypertension. DESIGN: The study is a crossover, open clinical trial (NCT00830843). SETTING: Neurointensive care unit of an academic hospital. PATIENTS: Thirteen patients with severe subarachnoid hemorrhage, (median Fisher scale 4), monitored on clinical indication with intracranial pressure device and a thermal diffusion probe for the assessment of regional cerebral blood flow. An intracranial pressure>18 mm Hg was an exclusion criterion. INTERVENTIONS: Cerebral and hemodynamic variables were assessed at three steps. Step 1: sedation with propofol 3-4 mg/kg/hr; step 2: after 1 hr of propofol discontinuation and isoflurane 0.8%; step 3: after 1 hr of propofol at the same previous infusion rate. Cerebral perfusion pressure and arterial PCO2 were maintained constant. Mean cerebral artery flow velocity and jugular vein oxygen saturation were measured at the end of each step. MEASUREMENTS AND MAIN RESULTS: Regional cerebral blood flow increased significantly during step 2 (39.3±29 mL/100 hg/min) compared to step 1 (20.8±10.7) and step 3 (24.7±8). There was no difference in regional cerebral blood flow comparing step 1 vs. step 3. No significant difference in intracranial pressure, mean cerebral artery transcranial Doppler velocity, PaCO2, cerebral perfusion pressure between the different steps. CONCLUSIONS: Isoflurane increases regional cerebral blood flow in comparison to propofol. Intracranial pressure did not change significantly in the population not affected by intracranial hypertension.
Anesthesiology · 1985 · 71 citations · open access
Local Application of 133Xenon for Measurement of Regional Cerebral Blood Flow (rCBF) during Halothane, Enflurane, and Isoflurane Anesthesia in Humans
AbstractIt is well known that halothane causes an increase in cerebral blood flow (CBF). In this study the effects of halothane, enflurane, and isoflurane on regional cerebral blood flow (rCBF) in humans were determined in the presence of 70% N2O at a combined MAC concentration of 1.5. CBF was determined in 24 patients from the washout of locally applied 133Xenon with the use of an external scintillation. All 24 patients (control n = 6, halothane n = 6, enflurane n = 6, and isoflurane n = 6) were undergoing neurosurgical procedures. All patients were anesthetized with thiopental, fentanyl, droperidol, and 70% N2O in oxygen and paralyzed with pancuronium. The measurements were performed after the dura had been opened and before definitive surgery. The first measurement was done in the absence of any volatile agent, and the wash-out curve was registered for 6 min. The second measurement was done after one of the volatile agents had been added for at least 20 min and had reached a concentration of 0.58% for halothane, 1.14% for enflurane, or 1.0% for isoflurane in the expiratory gases in order to obtain about 1.5 MAC with each volatile anesthetic. The anesthetic concentrations were measured with the Engström multigas analyzer EMMA. The physiologic variables changed very little throughout the period of observation. Body temperature, heart rate, blood pressure, PaCO2, and PaO2 were stable. Ephedrine was used to maintain a stable arterial pressure. At approximately 1.5 MAC, halothane (plus N2O) increased rCBF to nearly three times (166%) the control value, while enflurane induced only a slight increase (35%) in rCBF.(ABSTRACT TRUNCATED AT 250 WORDS)
Surgical Treatment of Atherosclerotic Occlusive Lesions in Patients with Cerebral Arterial Insufficiency
AbstractCerebral vascular disease, according to the results of arteriography, may be caused by extracranial arterial lesions in one third of the cases. Observations in 174 cases are described. The results of surgical treatment in 63 patients are presented and evaluated on the basis of restoration of circulation, clinical improvement, and survival. The implications regarding diagnosis and indications and contraindications for surgery are discussed.
Korean Journal of Anesthesiology · 2015 · 18 citations · open access
Effect of isoflurane post-treatment on tPA-exaggerated brain injury in a rat ischemic stroke model
AbstractBACKGROUND: Intravenous tissue-type plasminogen activator (tPA) is recognized as the standard treatment for ischemic stroke. However, its narrow therapeutic window and association with an increased risk of intracranial hemorrhage have required caution when used. In this context, several approaches are required to deal with the shortcomings of such a double-edged drug. Anesthetics are known to protect against ischemic reperfusion injury, and their protective role in ischemic post-conditioning is crucial for reducing ischemia-related injury. The aim of this study was to assess the effect of isoflurane post-treatment on intracranial hemorrhage and cerebral infarction after tPA treatment for transient cerebral ischemia. METHODS: Cerebral ischemia was modeled in male Sprague-Dawley rats (n = 32) by occluding the right middle cerebral artery for 1 h, followed by intravenous tPA administration. Rats were randomly divided into control and isoflurane post-treatment group, and isoflurane post-treatment group was post-treated by administering 1.5% isoflurane for 1 h from the start of reperfusion. Twenty-four h after reperfusion, neurobehavioral changes were assessed. The extent of cerebral infarction and intracranial hemorrhage were also assessed by quantification of infarction volume and cerebral hemoglobin concentration from brain tissue, respectively. RESULTS: Neurobehavioral testing showed better functional outcomes in the isoflurane post-treatment group than the control group. The extent of cerebral infarction and intracranial hemorrhage were both reduced in isoflurane post-treatment group compared to control group. CONCLUSIONS: Isoflurane post-treatment may mitigate infarction volume and intracranial hemorrhage in tPA-exaggerated brain injury. Our findings provide an encouraging novel approach for enhancing clinical outcomes in tPA-exaggerated brain injury.
Evidence of preservation of aerobic cerebral metabolism during halothane-induced hypotension
Abstract✓ The effect of halothane-induced profound systemic arterial hypotension on brain ischemia was evaluated by comparison with hypotension caused by oligemia and trimethaphan as well as nonhypotensive controls. Mean cerebral tissue lactate concentrations after halothane-induced hypotension at 5, 30, and 60 minutes were 4.34, 5.92, and 7.48 mM/kg. There was no significant difference between halothane and control animals during the experimental period. At 30 and 60 minutes, both oligemic and trimethaphan groups were higher than the control and halothane series. Definite protection from cerebral ischemia is provided by halothane during induced hypotension. Exact mechanisms of protection conveyed by halothane are unclear, but are probably not related to relative increased blood flow since cerebral vasodilation is maximal in these low blood-pressure ranges irrespective of etiology.
Ultraschall in der Medizin - European Journal of Ultrasound · 2008 · 4 citations
Einfluß der Halothan-Anästhesie auf zerebrale Blutflußgeschwindigkeiten bei Kindern
AbstractThe effects of halothane on the cerebral circulation were studied in 23 children during general anaesthesia. Blood flow velocity in one middle cerebral artery was recorded continuously by transcranial Doppler sonography. Furthermore arterial blood pressure, pulse rate, endtidal CO2partial pressure and endtidal halothane concentration were recorded. Mean flow velocities/mean arterial blood pressures were 79 cm x s-1/65 mmHg; 86 cm x s-1/61 mmHg; 78 cm x s-1/54 mmHg and 67 cm x s-1/48 mmHg with 1; 1.5; 2 and 2.5 per cent endtidal halothane concentrations, respectively. Endtidal CO2-partial pressure and pulse rate remained constant throughout the study. The higher cerebral blood flow velocities seen with 1.5 per cent halothane compared with 1 per cent can be explained by an increase in cerebral blood flow. The lower cerebral blood flow velocities and arterial blood pressure with 2.5 per cent halothane compared with 1.5 per cent indicate impaired cerebral autoregulation. However, cerebral blood flow appeared to be sufficient even with low arterial blood pressures.
Aberrant regulation of retinoic acid signaling genes in cerebral arterio venous malformation nidus and neighboring astrocytes
AbstractAbstract Background Cerebral arterio venous malformations (AVM) are a major causal factor for intracranial hemorrhage, which result in permanent disability or death. The molecular mechanisms of AVM are complex, and their pathogenesis remains an enigma. Current research on cerebral AVM is focused on characterizing the molecular features of AVM nidus to elucidate the aberrant signaling pathways. The initial stimuli that lead to the development of AVM nidus structures between a dilated artery and a vein are however not known. Methods In order to understand the molecular basis of development of cerebral AVM, we used in-depth RNA sequencing with the total RNA isolated from cerebral AVM nidus. Immunoblot and qRT-PCR assays were used to study the differential gene expression in AVM nidus, and immunofluorescence staining was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. Immunohistochemistry was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. Results The transcriptome study has identified 38 differentially expressed genes in cerebral AVM nidus, of which 35 genes were upregulated and 3 genes were downregulated. A final modular analysis identified an upregulation of ALDH1A2, a key rate-limiting enzyme of retinoic acid signaling pathway. Further analysis revealed that CYR61, a regulator of angiogenesis, and the target gene for retinoic acid signaling is upregulated in AVM nidus. We observed that astrocytes associated with AVM nidus are abnormal with increased expression of GFAP and Vimentin. Triple immunofluorescence staining of the AVM nidus revealed that CYR61 was also overexpressed in the abnormal astrocytes associated with AVM tissue. Conclusion Using high-throughput RNA sequencing analysis and immunostaining, we report deregulated expression of retinoic acid signaling genes in AVM nidus and its associated astrocytes and speculate that this might trigger the abnormal angiogenesis and the development of cerebral AVM in humans.
Profiling the unique protective properties of intracranial arterial endothelial cells
AbstractAbstract Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways. To gain insights into underlying mechanisms, we isolated post-mortem endothelial cells from both the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA) from the same individual (total of 15 individuals) with laser capture microdissection. RNA sequencing revealed a distinct molecular signature of the two endothelial cell populations of which the most prominent ones were validated by means of qPCR. Our data reveal for the first time that intracranial artery ECs exert an immune quiescent phenotype. Secondly, genes known to be involved in the response of ECs to damage (inflammation, differentiation, adhesion, proliferation, permeability and oxidative stress) are differentially expressed in intracranial ECs compared to extracranial ECs. Finally, Desmoplakin (DSP) and Hop Homeobox (HOPX), two genes expressed at a higher level in intracranial ECs, and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), a gene expressed at a lower level in intracranial ECs compared to extracranial ECs, were shown to be responsive to shear stress and/or hypoxia. With our data we present a set of intracranial-specific endothelial genes that may contribute to its protective phenotype, thereby supporting proper perfusion and consequently may preserve cognitive function. Deciphering the molecular regulation of the vascular bed in the brain may lead to the identification of novel potential intervention strategies to halt vascular associated disorders, such as atherosclerosis and vascular cognitive dysfunction.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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