Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke.

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

A history of stereotactic radiosurgery may predict failure of procedure following percutaneous glycerol rhizotomy for trigeminal neuralgia.

BACKGROUND: Both stereotactic radiosurgery (SRS) and percutaneous glycerol rhizotomy are excellent options to treat TN in patients unable to proceed with microvascular decompression. However, the influence of prior SRS on pain outcomes following rhizotomy is not well understood. METHODS: We retrospectively reviewed all patients undergoing percutaneous rhizotomy at our institution from 2011 to 2022. Only patients undergoing percutaneous glycerol rhizotomy following SRS (SRS-rhizotomy) or those undergoing primary glycerol rhizotomy were considered. We collected basic demographic, clinical, and pain characteristics for each patient. Additionally, we characterized pain presentation and perioperative complications. Immediate failure of procedure was defined as presence of TN pain symptoms within 1-week of surgery, and short-term failure was defined as presence of TN pain symptoms within 3-months of surgery. A multivariate logistic regression model was used to evaluate the relationship of a history SRS and failure of procedure following percutaneous glycerol rhizotomy. RESULTS: Of all patients reviewed, 30 had a history of SRS prior to glycerol rhizotomy whereas 371 underwent primary percutaneous glycerol rhizotomy. Patients with a history of SRS were more likely to endorse V3 pain symptoms, p = 0.01. Additionally, patients with a history of SRS demonstrated higher preoperative BNI pain scores, p = 0.01. Patients with a history of SRS were more likely to endorse preoperative numbness, p < 0.0001. A history of SRS was independently associated with immediate failure [OR = 5.44 (2.06-13.8), p < 0.001] and short-term failure of glycerol rhizotomy [OR = 2.41 (1.07-5.53), p = 0.03]. Additionally, increasing age was found to be associated with lower odds of short-term failure of glycerol rhizotomy [OR = 0.98 (0.97-1.00), p = 0.01] CONCLUSIONS: A history of SRS may increase the risk of immediate and short-term failure following percutaneous glycerol rhizotomy. These results may be of use to patients who are poor surgical candidates and require multiple noninvasive/minimally invasive options to effectively manage their pain.

Relative anemia and perioperative stroke in children with moyamoya.

OBJECTIVES: Surgical revascularization for moyamoya arteriopathy decreases long-term stroke risk but carries a risk of perioperative ischemic complications. We aimed to evaluate modifiable stroke risk factors in children undergoing surgical revascularization for moyamoya. MATERIALS AND METHODS: In this exploratory, single-center, retrospective cohort study, medical records of pediatric patients undergoing surgical revascularization for moyamoya arteriopathy at our center between 2003 and 2021 were reviewed. Candidate modifiable risk factors were analyzed for association with perioperative stroke, defined as ischemic stroke ≤7 days after surgery. RESULTS: We analyzed 53 surgeries, consisting of 39 individual patients undergoing indirect surgical revascularization of 74 hemispheres. Perioperative ischemic stroke occurred following five surgeries (9.4%). There were no instances of hemorrhagic stroke. Larger pre-to-postoperative decreases in hemoglobin (OR 3.90, p=0.017), hematocrit (OR 1.69, p=0.012) and blood urea nitrogen (OR 1.83, p=0.010) were associated with increased risk of perioperative ischemic stroke. Weight-adjusted intraoperative blood loss was not associated with risk of perioperative ischemic stroke (OR 0.94, p=0.796). Among children with sickle cell disease, all of whom underwent exchange transfusion within one week prior to surgery, none experienced perioperative stroke. CONCLUSIONS: Decreases in hemoglobin, hematocrit, and blood urea nitrogen between the preoperative and postoperative periods are associated with increased risk of perioperative stroke. These novel findings suggest that dilutional anemia, possibly due to standardly administered hyperhydration, may increase the risk of perioperative stroke in some children with moyamoya. Further work optimizing both mean arterial pressure and oxygen-carrying capacity in these patients, including consideration of alternative blood transfusion thresholds, is necessary.

Same-day versus staged revascularization of bilateral moyamoya arteriopathy in pediatric patients.

PURPOSE: To compare the outcomes of conducting left and right hemisphere surgical revascularization on the same day versus different days for bilateral pediatric moyamoya arteriopathy patients. METHODS: We retrospectively analyzed mortality, stroke, and transient neurologic event (TNE) rates in North American bilateral pediatric moyamoya arteriopathy patients who underwent bilateral cerebral revascularization. RESULTS: A total of 38 pediatric (≤ 18 years old) patients at our institution underwent bilateral cerebral revascularization for moyamoya arteriopathy. Of these patients, 24 (63.2%) had both operations on the same day and 14 (36.8%) had the two operations on different days. The average length of stay for patients who underwent same-day bilateral revascularization was 6.9 ± 2.0 days and the average length of stay for each operation for patients who underwent staged bilateral revascularization was 4.5 ± 1.4 days, p = 0.001. While there were 7 (14.6%) postoperative strokes in patients who had both hemispheres revascularized on the same day, 0 (0%) strokes occurred in hemispheres after they had been operated on in the staged cohort, p = 0.042. Additionally, the postoperative stroke-free survival time in the ipsilateral hemisphere and TNE-free survival time were significantly longer in patients in the staged revascularization cohort. CONCLUSION: Same-day bilateral revascularization was associated with longer length of stay per operation, higher rate of ipsilateral stroke, and shorter postoperative TNE-free and stroke-free survival time in the revascularized hemisphere.

Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2.

The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in p53-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.

The neurosurgical management of Severe Hemophilia A and Moyamoya (SHAM): challenges, strategies, and literature review.

INTRODUCTION: Severe Hemophilia A and Moyamoya arteriopathy (SHAM syndrome) is a rare genetic disorder caused by deletion of portions of the cytogenic band Xq28. A case of SHAM syndrome requiring bilateral cerebral revascularization is described with an emphasis on perioperative management. CASE REPORT: A 5-year-old boy with severe hemophilia A complicated by factor VIII inhibition presented with right-sided weakness. Imaging revealed multiple strokes and vascular changes consistent with Moyamoya disease. The patient underwent two-staged indirect cerebral bypass revascularizations, first on the left side and several months later on the right. Perioperative management required balancing the administration of agents to prevent coagulopathy and perioperative hemorrhage while mitigating the risk of thromboembolic events associated with bypass surgery. Despite a multidisciplinary effort by the neurosurgery, hematology, critical care, and anesthesiology teams, the post-operative course after both surgeries was complicated by stroke. Fortunately, the patient recovered rapidly to his preoperative functional baseline. CONCLUSION: We describe a rare case of SHAM syndrome in a pediatric patient who required bilateral revascularizations and discuss strategies for managing the perioperative risk of hemorrhage and stroke. We also review existing literature on SHAM syndrome.

Isolated aneurysms of the spinal circulation: a systematic review of the literature.

Aneurysms arising in the spinal circulation are rare and underreported. The objective of this study was to systematically review the English literature on different aspects of isolated spinal aneurysms using the PubMed, Ovid MEDLINE, and Google Scholar databases. Eighty-two papers reporting 107 individual patient cases were included. Most isolated spinal aneurysms have a fusiform morphology, and are most commonly found in the anterior spinal artery at the thoracic or cervical levels. Subarachnoid hemorrhage is the most common form of presentation, and sudden onset back pain is the most common initial symptom. The diagnosis of spinal aneurysms requires a high degree of clinical suspicion. Because of their small size, they can be missed on CT/MR angiography and spinal angiogram may be employed. Treatment of spinal aneurysms should be individualized on a case-by-case basis. Conservative management can be a valid option in spinal aneurysms where the risk of treatment is high. Surgical or endovascular intervention may be indicated in cases of significant or progressive neurologic decline due aneurysmal mass effect, or progressive growth of the aneurysm despite conservative treatment.

Application of unruptured aneurysm scoring systems to a cohort of ruptured aneurysms: are we underestimating rupture risk?

The predictive values of current risk stratification scales such as the Unruptured Intracranial Aneurysm Treatment Score (UIATS) and the PHASES score are debatable. We evaluated these scores using a cohort of ruptured intracranial aneurysms to simulate their management recommendations had the exact same patients presented prior to rupture. A prospectively maintained database of ruptured saccular aneurysm patients presenting to our institution was used. The PHASES score was calculated for 992 consecutive patients presenting between January 2002 and December 2018, and the UIATS was calculated for 266 consecutive patients presenting between January 2013 and December 2018. A shorter period was selected for the UIATS cohort given the larger number of variables required for calculation. Clinical outcomes were compared between UIATS-recommended "observation" aneurysms and all other aneurysms. Out of 992 ruptured aneurysms, 54% had a low PHASES score (≤5). Out of the 266 ruptured aneurysms, UIATS recommendations were as follows: 68 (26%) "observation," 97 (36%) "treatment," and 101 (38%) "non-definitive." The UIATS conservative group of patients developed more SAH-related complications (78% vs. 65%, p=0.043), had a higher rate of non-home discharge (74% vs. 46%, p<0.001), and had a greater incidence of poor functional status (modified Rankin scale >2) after 12-18 months (68% vs. 51%, p=0.014). Current predictive scoring systems for unruptured aneurysms may underestimate future rupture risk and lead to more conservative management strategies in some patients. Patients that would have been recommended for conservative therapy were more likely to have a worse outcome after rupture.

Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation.

RATIONALE: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. OBJECTIVE: We have investigated the role of IPMK in regulating angiogenesis. METHODS AND RESULTS: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. CONCLUSIONS: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.

Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease.

Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.

Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions.

Nuclear factor κB (NF-κB) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-κB are mediated by hydrogen sulfide (H(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-α treatment triples H(2)S generation by stimulating binding of SP1 to the CSE promoter. H(2)S generated by CSE stimulates DNA binding and gene activation of NF-κB, processes that are abolished in CSE-deleted mice. As CSE deletion leads to decreased glutathione levels, resultant oxidative stress may contribute to alterations in CSE mutant mice. H(2)S acts by sulfhydrating the p65 subunit of NF-κB at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-α treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-κB are markedly diminished. Thus, sulfhydration of NF-κB appears to be a physiologic determinant of its antiapoptotic transcriptional activity.

R2eD AVM Score.

Background and Purpose- The management of unruptured brain arteriovenous malformations remains unclear. Using a large cohort to determine risk factors predictive of hemorrhagic presentation of arteriovenous malformations, this study aims to develop a predictive tool that could guide hemorrhage risk stratification. Methods- A database of 789 arteriovenous malformation patients presenting to our institution between 1990 and 2017 was used. A hold-out method of model validation was used, whereby the data was randomly split in half into training and validation data sets. Factors significant at the univariable level in the training data set were used to construct a model based on multivariable logistic regression. Model performance was assessed using receiver operating curves on the training, validation, and complete data sets. The predictors and the complete data set were then used to derive a risk prediction formula and a practical scoring system, where every risk factor was worth 1 point except race, which was worth 2 points (total score varies from 0 to 6). The factors are summarized by R2eD arteriovenous malformation (acronym: R2eD AVM). Results- In 755 patients with complete data, 272 (36%) presented with hemorrhage. From the training data set, a model was derived containing the following risk factors: nonwhite race (odds ratio [OR]=1.8; P=0.02), small nidus size (OR=1.47; P=0.14), deep location (OR=2.3; P<0.01), single arterial feeder (OR=2.24; P<0.01), and exclusive deep venous drainage (OR=2.07; P=0.02). Area under the curve from receiver operating curve analysis was 0.702, 0.698, and 0.685 for the training, validation, and complete data sets, respectively. In the entire study population, the predicted probability of hemorrhagic presentation increased in a stepwise manner from 16% for patients with no risk factors (score of 0) to 78% for patients having all the risk factors (score of 6). Conclusions- The final model derived from this study can be used as a predictive tool that supplements clinical judgment and aids in patient counseling.

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1.

The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.

Huntington's disease: Neural dysfunction linked to inositol polyphosphate multikinase.

Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.

Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNA repair and cell death.

Inositol polyphosphates containing an energetic pyrophosphate bond are formed primarily by a family of three inositol hexakisphosphate (IP6) kinases (IP6K1-3). The Cullin-RING ubiquitin ligases (CRLs) regulate diverse biological processes through substrate ubiquitylation. CRL4, comprising the scaffold Cullin 4A/B, the E2-interacting Roc1/2, and the adaptor protein damage-specific DNA-binding protein 1, is activated by DNA damage. Basal CRL4 activity is inhibited by binding to the COP9 signalosome (CSN). UV radiation and other stressors dissociate the complex, leading to E3 ligase activation, but signaling events that trigger signalosome dissociation from CRL4 have been unclear. In the present study, we show that, under basal conditions, IP6K1 forms a ternary complex with CSN and CRL4 in which IP6K1 and CRL4 are inactive. UV dissociates IP6K1 to generate IP7, which then dissociates CSN-CRL4 to activate CRL4. Thus, IP6K1 is a novel CRL4 subunit that transduces UV signals to mediate disassembly of the CRL4-CSN complex, thereby regulating nucleotide excision repair and cell death.

A comparative study of perioperative complications between transforaminal versus posterior lumbar interbody fusion in degenerative lumbar spondylolisthesis.

BACKGROUND: Both posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) are accepted surgical techniques for the treatment of degenerative lumbar spondylolisthesis (DLS). However, it is still unclear one technique offers distinct advantages over the other. OBJECTIVE: A retrospective study was performed to compare perioperative complications and functional outcomes of patients undergoing TLIF versus PLIF for DLS. METHODS: A total of 226 consecutive patients who underwent surgery for treatment of DLS at three institutions were evaluated from January 2012 to December 2014. In this series, 125 patients underwent PLIF and 101 received TLIF. The operative time, blood loss, allogeneic blood transfusion rate and perioperative complications (including re-operative rate, nerve root injury, dural tear, wound infection) were compared between the two groups. Pain (VAS) and functional outcomes of patients (Kirkaldy-Willis criteria) were quantified before surgery and 1 week after surgery. RESULTS: Patients involved in the two groups had similar baseline demographic, clinical and radiographic characteristics. The PLIF group was associated with a higher incidence of post-operative iatrogenic nerve root dysfunction [12 cases (9.6 %) versus 2 cases (1.9 %), P = 0.018] and dural tears [15 cases (12 %) versus 4 cases (3.9 %), P = 0.030]. The re-operation rate was significantly higher in patients undergoing PLIF [13 cases (10.4 %) versus 2 cases (1.9 %), P = 0.011]. In addition, intra-operative blood loss, operative times, and allogeneic blood transfusion rates were higher in the PLIF group when compared to the TLIF group (P < 0.05). The wound infection rate of the PLIF group was similar to that of the TLIF group (7.2 versus 5.0 %, P = 0.486). VAS scores were decreased from 7.08 ± 1.13 to 2.84 ± 0.89 in the PLIF group, and from 7.18 ± 1.09 to 2.84 ± 0.91 in the TLIF group, respectively (P = 0.32). 85.6 % of patients in the TLIF group had good or excellent functional outcomes within the first post-operative week compared to 83.2 % in the PLIF group (P = 0.64). CONCLUSION: Both PLIF and TLIF were equally beneficial in improving short-term functional outcomes for patients with DLS. However, PLIFs were associated with statistically significant higher incidences of nerve root injury, dural tears, allogeneic blood transfusion, increased intra-operative times, blood loss and re-operations. Therefore, caution should be exercised when considering PLIFs.

Total en bloc spondylectomy for locally aggressive and primary malignant tumors of the lumbar spine.

PURPOSE: To report outcomes after total en bloc spondylectomy (TES) for primary aggressive/malignant tumors of the lumbar spine. METHODS: We performed a retrospective review of 23 neurosurgical patients operated between 2004 and 2014. Outcomes included perioperative complication rates and reoperation rates for instrumentation failure. The relationship between patient/operative parameters and complication development/instrumentation failure was investigated. RESULTS: There were 15 men (65.2 %) and eight women (24.8 %), with a median of 47 years. The most common tumor was chordoma in 11 patients (47.8 %), followed by sarcoma in four (17.4 %), and giant cell tumor in three (13.0 %). All patients but one underwent a two-staged operation; median total estimated blood loss was 3200 mL and median total operative time was 18.5 h. Fifteen patients developed at least one perioperative complication (65.2 %), with the most common being wound infection and ileus (26.1 % each). There was one case of intraoperative iliac vein injury (4.4 %). Instrumentation failure occurred in 9 patients (39.1 %) at a median time of 23 months after index spondylectomy. Following logistic regression, there were no factors associated with complication development. On the other hand, postoperative radiation was significantly associated with instrumentation failure (OR 7.49; 95 % CI, 1.02-54.9). Local recurrence and 5-year survival was 8.7 and 84.4 %, respectively. Median follow-up time was 50 months. CONCLUSIONS: Although favorable oncological outcomes after en bloc resection of spinal tumors may be achieved in terms of recurrence and survival, TES in the lumbar spine remains a challenging procedure. Future investigation into complication avoidance and reconstruction techniques is encouraged.

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction.

Profound induction of immediate early genes (IEGs) by neural activation is a critical determinant for plasticity in the brain, but intervening molecular signals are not well characterized. We demonstrate that inositol polyphosphate multikinase (IPMK) acts noncatalytically as a transcriptional coactivator to mediate induction of numerous IEGs. IEG induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters. Interestingly, IPMK regulation of CBP recruitment and IEG induction does not require its catalytic activities. Dominant-negative constructs, which prevent IPMK-CBP binding, substantially decrease IEG induction. As IPMK is ubiquitously expressed, its epigenetic regulation of IEGs may influence diverse nonneural and neural biologic processes.

Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB.

The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP(3) as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP(3) generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.