Cocaine use is associated with cerebral white matter hyperintensities in HIV disease.

BACKGROUND: White matter hyperintensities (WMH), a marker of cerebral small vessel disease and predictor of cognitive decline, are observed at higher rates in persons with HIV (PWH). The use of cocaine, a potent central nervous system stimulant, is disproportionately common in PWH and may contribute to WMH. METHODS: The sample included of 110 PWH on antiretroviral therapy. Fluid-attenuated inversion recovery (FLAIR) and T1-weighted anatomical MRI scans were collected, along with neuropsychological testing. FLAIR images were processed using the Lesion Segmentation Toolbox. A hierarchical regression model was run to investigate predictors of WMH burden [block 1: demographics; block 2: cerebrovascular disease (CVD) risk; block 3: lesion burden]. RESULTS: The sample was 20% female and 79% African American with a mean age of 45.37. All participants had persistent HIV viral suppression, and the median CD4+ T-cell count was 750. Nearly a third (29%) currently used cocaine regularly, with an average of 23.75 (SD = 20.95) days in the past 90. In the hierarchical linear regression model, cocaine use was a significant predictor of WMH burden (ß = .28). WMH burden was significantly correlated with poorer cognitive function (r = -0.27). Finally, higher WMH burden was significantly associated with increased serum concentrations of interferon-γ-inducible protein 10 (IP-10) but lower concentrations of myeloperoxidase (MPO); however, these markers did not differ by COC status. CONCLUSIONS: WMH burden is associated with poorer cognitive performance in PWH. Cocaine use and CVD risk independently contribute to WMH, and addressing these conditions as part of HIV care may mitigate brain injury underlying neurocognitive impairment.

Gold Nanostars Obviate Limitations to Laser Interstitial Thermal Therapy (LITT) for the Treatment of Intracranial Tumors.

PURPOSE: Laser interstitial thermal therapy (LITT) is an effective minimally invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT. EXPERIMENTAL DESIGN: The impact of GNS on LITT coverage capacity was tested in ex vivo models using clinical LITT equipment and agarose gel-based phantoms of control and GNS-infused central "tumors." In vivo accumulation of GNS and amplification of ablation were tested in murine intracranial and extracranial tumor models followed by intravenous GNS injection, PET/CT, two-photon photoluminescence, inductively coupled plasma mass spectrometry (ICP-MS), histopathology, and laser ablation. RESULTS: Monte Carlo simulations demonstrated the potential of GNS to accelerate and specify thermal distributions. In ex vivo cuboid tumor phantoms, the GNS-infused phantom heated 5.5× faster than the control. In a split-cylinder tumor phantom, the GNS-infused border heated 2× faster and the surrounding area was exposed to 30% lower temperatures, with margin conformation observed in a model of irregular GNS distribution. In vivo, GNS preferentially accumulated within intracranial tumors on PET/CT, two-photon photoluminescence, and ICP-MS at 24 and 72 hours and significantly expedited and increased the maximal temperature achieved in laser ablation compared with control. CONCLUSIONS: Our results provide evidence for use of GNS to improve the efficiency and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors and amplification of laser ablation, and the GNS-infused phantom experiments demonstrate increased rates of heating, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.

Durable responses in patients with HER2+ breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan.

Leptomeningeal metastases (LM) are a devastating complication of HER2 + metastatic breast cancer (MBC), with no effective treatments. In a case series of 8 patients with heavily pretreated HER2 + MBC and progressing LM, all 8 patients (100%) derived clinical benefit from Trastuzumab deruxtecan (TDXd), and 4 patients (50%) had an objective partial response based on formal neuroradiology MRI reads using the EORTC/RANO-LM Revised-Scorecard. T-DXd warrants further study in LM in HER2 + MBC and solid tumors where T-DXd may be active.

The Acute Effects of Time-Varying Caloric Vestibular Stimulation as Assessed With fMRI.

We describe preliminary results from the application of time-varying caloric vestibular stimulation (tvCVS) to volunteers during a continuous blood oxygen level dependent (BOLD) functional MRI (fMRI) acquisition, recording baseline, during-tvCVS and post-tvCVS epochs. The modifications necessary to enable the use of this novel device in a 3-Tesla magnetic field are discussed. Independent component analysis (ICA) was used as a model-free method to highlight spatially and temporally coherent brain networks. The ICA results are consistent with tvCVS induction being mediated principally by thermoconvection in the vestibular labyrinth and not by direct thermal effects. The activation of hub networks identified by ICA is consistent with the concept of sensory neuromodulation, which posits that a modulatory signal introduced to a sensory organ is able to traverse the regions innervated (directly and indirectly) by that organ, while being transformed so as to be "matched" to regional neuronal dynamics. The data suggest that regional neurovascular coupling and a systemic cerebral blood flow component account for the BOLD contrast observed. The ability to modulate cerebral hemodynamics is of significant interest. The implications of these initial findings for the use of tvCVS therapeutically are discussed.

Neuroprotective Pentapeptide, CN-105, Improves Outcomes in Translational Models of Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease for which there are no approved pharmacological interventions that improve outcomes. Apolipoprotein E (apoE) has emerged as a promising therapeutic target given its isoform-specific neuroprotective properties and ability to modify neuroinflammatory responses. We developed a 5-amino acid peptide, CN-105, that mimics the polar face of the apoE helical domain involved in receptor interactions, readily crosses the blood-brain barrier, and improves outcomes in well-established preclinical ICH models. In the current study, we investigated the therapeutic potential of CN-105 in translational ICH models that account for hypertensive comorbidity, sex, species, and age. METHODS: In three separate experiments, we delivered three intravenous doses of CN-105 (up to 0.20 mg/kg) or vehicle to hypertensive male BPH/2 J mice, spontaneously hypertensive female rats, or 11-month-old male mice within 24-h of ICH. Neuropathological and neurobehavioral outcomes were determined over 3, 7, and 9 days, respectively. RESULTS: In spontaneously hypertensive male mice, there was a significant dose-dependent effect of CN-105 on vestibulomotor function at 0.05 and 0.20 mg/kg doses (p < 0.05; 95% CI: 0.91-153.70 and p < 0.001; 95% CI: 49.54-205.62), while 0.20 mg/kg also improved neuroseverity scores (p < 0.05; 95% CI: 0.27-11.00) and reduced ipsilateral brain edema (p < 0.05; 95% CI: - 0.037 to - 0.001). In spontaneously hypertensive female rats, CN-105 (0.05 mg/kg) had a significant effect on vestibulomotor function (p < 0.01; η2 = 0.093) and neuroseverity scores (p < 0.05; η2 = 0.083), and reduced contralateral edema expansion (p < 0.01; 95% CI: - 1.41 to - 0.39). In 11-month-old male mice, CN-105 had a significant effect on vestibulomotor function (p < 0.001; η2 = 0.111) but not neuroseverity scores (p > 0.05; η2 = 0.034). CONCLUSIONS: Acute treatment with CN-105 improves outcomes in translational ICH models independent of sex, species, age, or hypertensive comorbidity.

Author Correction: Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Plasmonic gold nanostar-mediated photothermal immunotherapy for brain tumor ablation and immunologic memory.

Brain tumors present unique therapeutic challenges and they include glioblastoma (GBM) and metastases from cancers of other organs. Current treatment options are limited and include surgical resection, radiation therapy, laser interstitial thermal therapy and chemotherapy. Although much research has been done on the development of immune-based treatment platforms, only limited success has been demonstrated. Herein, we demonstrate a novel treatment of GBM through the use of plasmonic gold nanostars (GNS) as photothermal inducers for synergistic immuno photothermal nanotherapy (SYMPHONY), which combines treatments using gold nanostar and laser-induced photothermal therapy with checkpoint blockade immunotherapy. In the treatment of a murine flank tumor model with the CT-2A glioma cell line, SYMPHONY demonstrated the capability of producing long-term survivors that rejects rechallenge with cancer cells, heralding the successful emergence of immunologic memory. This study is the first to investigate the use of this novel therapy for the treatment of GBM in a murine model.

Annexin A1 Bioactive Peptide Promotes Resolution of Neuroinflammation in a Rat Model of Exsanguinating Cardiac Arrest Treated by Emergency Preservation and Resuscitation.

Neuroinflammation initiated by damage-associated molecular patterns, including high mobility group box 1 protein (HMGB1), has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma. Emergency preservation and resuscitation (EPR) is a novel method of resuscitation for victims of exsanguinating cardiac arrest, shown in preclinical studies to improve survival with acceptable neurological recovery. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has emerged as a key regulator of metabolic and energy stress response pathways in the brain and a pharmacological target to induce a neuronal pro-survival phenotype. This study aims to examine whether systemic administration of an Annexin-A1 bioactive peptide (ANXA1sp) could resolve neuroinflammation and induce sirtuin-3 regulated cytoprotective pathways in a novel rat model of exsanguinating cardiac arrest and EPR. Adult male rats underwent hemorrhagic shock and ventricular fibrillation, induction of profound hypothermia, followed by resuscitation and rewarming using cardiopulmonary bypass (EPR). Animals randomly received ANXA1sp (3 mg/kg, in divided doses) or vehicle. Neuroinflammation (HMGB1, TNFα, IL-6, and IL-10 levels), cerebral cell death (TUNEL, caspase-3, pro and antiapoptotic protein levels), and neurologic scores were assessed to evaluate the inflammation resolving effects of ANXA1sp following EPR. Furthermore, western blot analysis and immunohistochemistry were used to interrogate the mechanisms involved. Compared to vehicle controls, ANXA1sp effectively reduced expression of cerebral HMGB1, IL-6, and TNFα and increased IL-10 expression, which were associated with improved neurological scores. ANXA1sp reversed EPR-induced increases in expression of proapoptotic protein Bax and reduction in antiapoptotic protein Bcl-2, with a corresponding decrease in cerebral levels of cleaved caspase-3. Furthermore, ANXA1sp induced autophagic flux (increased LC3II and reduced p62 expression) in the brain. Mechanistically, these findings were accompanied by upregulation of the mitochondrial protein deacetylase Sirtuin-3, and its downstream targets FOXO3a and MnSOD in ANXA1sp-treated animals. Our data provide new evidence that engaging pro-resolving pharmacological strategies such as Annexin-A1 biomimetic peptides can effectively attenuate neuroinflammation and enhance the neuroprotective effects of EPR after exsanguinating cardiac arrest.

Sex Differences in Gene and Protein Expression After Intracerebral Hemorrhage in Mice.

Sex dimorphism has been demonstrated after experimental intracerebral hemorrhage (ICH). Decreased mortality and improved neurobehavioral outcomes occur in female compared to male mice after intrastriatal autologous blood or collagenase injection. Sex-specific differences in post-ICH gene and protein expression may provide mechanistic insight into this phenomenon. Ten- to 12-week-old C57BL/6 male (M) and female in high estrous state (HE-F) underwent left intrastriatal collagenase injection. We assessed neurobehavioral outcomes over the first 30 days, hematoma volume and cerebral edema evolution over the first 24 h, and transcriptomic gene and protein expression at pre-selected time points during the acute phase of injury. Genome-wide expression profiling was performed with Affymetrix GeneChip Mouse Genome 2.0 Probes, and proteomics analyses were performed using mass spectroscopy. Sex does not affect hemorrhage evolution, but female sex is associated with improved neurobehavioral recovery after ICH. A total of 7037 probes qualified for our filtering criteria, representing 5382 mapped genes and 256 unmapped genes. Female-unique pathways involved cell development, growth, and proliferation, while male-unique pathways involved molecular degradation. At 6 and 24 h post-ICH, differential expression was observed in 850 proteins vs baseline in males, 608 proteins vs baseline in females, and 1 protein in females vs males. Female sex is associated with improved neurobehavioral recovery, and differential gene and protein expression after intrastriatal collagenase injection.

BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.

BACKGROUND: Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitative trait loci in mice, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. METHODS: We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2-associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia. RESULTS: We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6-Lsq1-3). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein- (n=29) expressing animals. BAG3Ile81, but not BAG3Met81, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus-BAG3Ile81 (n=9), but not BAG3Met81 (n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. CONCLUSIONS: Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.

Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.

Presently, no pharmacological treatments have been demonstrated to improve long-term functional outcomes following intracerebral hemorrhage (ICH). Clinical evidence associates apolipoprotein E (apoE) genotype with ICH incidence and outcome. While apoE modifies neuroinflammatory responses through its adaptive role in glial downregulation, intact apoE holoprotein is too large to cross the blood-brain barrier (BBB). Therefore, we developed a 5-amino acid peptide - CN-105 - that mimics the polar face of the apoE helical domain involved in receptor interactions. In the current study, we investigated the therapeutic potential of CN-105 in a mouse model of ICH. Three doses of CN-105 (0.05 mg/kg) was administered by tail vein injection within 24 hours after ICH induction. Functional assessment showed durable improvement in vestibulomotor performance after CN-105 treatment, as quantified by increased Rotarod latencies on Days 1-5 post-ICH, and long-term improvement in neurocognitive performance, as quantified by reduced Morris water maze latencies on Days 29-32 post-ICH. Further, brain water content was significantly reduced, neuroinflammation was decreased and hippocampal CA3 neuronal survival was increased, although hemorrhage volume was not affected by CN-105. We concluded, therefore, that pentapeptide CN-105 improved short- and long-term neurobehavioral outcomes in a murine model of ICH, suggesting therapeutic potential for patients with acute ICH.

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage.

BACKGROUND: Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats. METHODS: ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury. RESULTS: Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-x03BA;B p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected. CONCLUSIONS: Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.

Anticancer therapeutic potential of Mn porphyrin/ascorbate system.

Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of Mn(III)P/Mn(II)P redox couple, ranged from -200 to +350 mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0 mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5 µM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL-100 cells. Bell-shape relationship, essentially identical to vo(Asc)oxvs E1/2, was also demonstrated between MnP/Asc-controlled cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1-relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)oxvs E1/2 relationships and cellular toxicity, MnTE-2-PyP(5+) was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP(5+) were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4 g/kg) and MnTE-2-PyP(5+) (0.2mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP(5+) or ascorbate alone. About 7-fold higher accumulation of MnTE-2-PyP(5+) in tumor vs normal tissue was found to contribute largely to the anticancer effect.

Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise.

Exercise has been shown to improve postischemia perfusion of normal tissues; we investigated whether these effects extend to solid tumors. Estrogen receptor-negative (ER-, 4T1) and ER+ (E0771) tumor cells were implanted orthotopically into syngeneic mice (BALB/c, N = 11-12 per group) randomly assigned to exercise or sedentary control. Tumor growth, perfusion, hypoxia, and components of the angiogenic and apoptotic cascades were assessed by MRI, immunohistochemistry, western blotting, and quantitative polymerase chain reaction and analyzed with one-way and repeated measures analysis of variance and linear regression. All statistical tests were two-sided. Exercise statistically significantly reduced tumor growth and was associated with a 1.4-fold increase in apoptosis (sedentary vs exercise: 1544 cells/mm(2), 95% CI = 1223 to 1865 vs 2168 cells/mm(2), 95% CI = 1620 to 2717; P = .048), increased microvessel density (P = .004), vessel maturity (P = .006) and perfusion, and reduced intratumoral hypoxia (P = .012), compared with sedentary controls. We also tested whether exercise could improve chemotherapy (cyclophosphamide) efficacy. Exercise plus chemotherapy prolonged growth delay compared with chemotherapy alone (P < .001) in the orthotopic 4T1 model (n = 17 per group). Exercise is a potential novel adjuvant treatment of breast cancer.

Intrastriatal injection of autologous blood or clostridial collagenase as murine models of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a common form of cerebrovascular disease and is associated with significant morbidity and mortality. Lack of effective treatment and failure of large clinical trials aimed at hemostasis and clot removal demonstrate the need for further mechanism-driven investigation of ICH. This research may be performed through the framework provided by preclinical models. Two murine models in popular use include intrastriatal (basal ganglia) injection of either autologous whole blood or clostridial collagenase. Since, each model represents distinctly different pathophysiological features related to ICH, use of a particular model may be selected based on what aspect of the disease is to be studied. For example, autologous blood injection most accurately represents the brain's response to the presence of intraparenchymal blood, and may most closely replicate lobar hemorrhage. Clostridial collagenase injection most accurately represents the small vessel rupture and hematoma evolution characteristic of deep hemorrhages. Thus, each model results in different hematoma formation, neuroinflammatory response, cerebral edema development, and neurobehavioral outcomes. Robustness of a purported therapeutic intervention can be best assessed using both models. In this protocol, induction of ICH using both models, immediate post-operative demonstration of injury, and early post-operative care techniques are demonstrated. Both models result in reproducible injuries, hematoma volumes, and neurobehavioral deficits. Because of the heterogeneity of human ICH, multiple preclinical models are needed to thoroughly explore pathophysiologic mechanisms and test potential therapeutic strategies.

Effects of deep hypothermic circulatory arrest on the blood brain barrier in a cardiopulmonary bypass model--a pilot study.

BACKGROUND: Neurologic injury is common after cardiac surgery and disruption of the blood brain barrier (BBB) has been proposed as a contributing factor. We sought to study BBB characteristics in a rodent model of cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). METHODS: Adult rats were subjected to CPB/DHCA or to sham surgery. Analysis included Western blotting of relevant BBB proteins in addition to in vivo brain magnetic resonance imaging (MRI) with a clinically used low-molecular contrast agent. RESULTS: While quantitative analysis of BBB proteins revealed similar expression levels, MRI showed evidence of BBB disruption after CPB/DHCA compared to sham surgery. CONCLUSIONS: Combining molecular BBB analysis and MRI technology in a rodent model is a highly translatable approach to study adverse neurologic outcomes following CPB/DHCA.

pH-sensitive NMDA inhibitors improve outcome in a murine model of SAH.

BACKGROUND: Despite intensive research, neurological morbidity from delayed cerebral ischemia remains common after aneurysmal subarachnoid hemorrhage (SAH). In the current study, we evaluate the neuroprotective effects of a pH-dependent GluN2B subunit-selective NMDA receptor antagonist in a murine model of SAH. METHODS: Following induction of SAH, 12 ± 2 week old male C57-BL/6 mice received NP10075, a pH-dependent NMDA receptor antagonist, or vehicle. In a separate series of experiments, NP10075 and the non-pH sensitive NMDA antagonist, NP10191, were administered to normoglycemic and hyperglycemic mice. Both histological (right middle cerebral artery diameter, NeuN, and Fluoro-Jade B staining) and functional endpoints (rotarod latency and neuroseverity score) were evaluated to assess the therapeutic benefit of NP10075. RESULTS: Administration of NP10075 was well tolerated and had minimal hemodynamic effects following SAH. Administration of the pH-sensitive NMDA antagonist NP10075, but not NP10191, was associated with a durable improvement in the functional performance of both normoglycemic and hyperglycemic animals. NP10075 was also associated with a reduction in vasospasm in the middle cerebral artery associated with hemorrhage. There was no significant difference between treatment with nimodipine + NP10075, as compared to NP10075 alone. CONCLUSIONS: These data demonstrate that use of a pH-dependent NMDA antagonist has the potential to work selectively in areas of ischemia known to undergo acidic pH shifts, and thus may be associated with selective regional efficacy and fewer behavioral side effects than non-selective NMDA antagonists.

ApolipoproteinE mimetic peptides improve outcome after focal ischemia.

Growing clinical evidence implicates isoform-specific effects of apolipoprotein E (apoE) in reducing neuroinflammation and mediating adaptive responses following ischemic and traumatic brain injury. However, the intact apoE holoprotein does not cross the blood-brain barrier and thus has limited therapeutic potential. We have created a small peptide, COG1410 (acetyl-AS-Aib-LRKL-Aib-KRLL-amide), derived from the apoE receptor-binding region. COG1410 retains the anti-inflammatory and neuroprotective biological properties of the intact holoprotein and penetrates the blood-brain barrier. In the current study, we utilized a murine model of transient focal cerebral ischemia and reperfusion to demonstrate that intravenous (IV) administration of COG1410 reduces infarct volume and radiographic progression of infarct, and improves functional outcome as assessed by rotarod when delivered up to 4h after ischemia onset.