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Yuxia Han, Don Seyfried, Yuling Meng, Dongmei Yang, Lonni Schultz, Michael Chopp and Donald Seyfried

OBJECTIVE

Previous studies have demonstrated that transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after experimental intracerebral hemorrhage (ICH). In this study the authors tested the hypothesis that administration of multipotent MSC-derived exosomes promotes functional recovery, neurovascular remodeling, and neurogenesis in a rat model of ICH.

METHODS

Sixteen adult male Wistar rats were subjected to ICH via blood injection into the striatum, followed 24 hours later by tail vein injection of 100 μg protein of MSC-derived exosomes (treatment group, 8 rats) or an equal volume of vehicle (control group, 8 rats); an additional 8 rats that had identical surgery without blood infusion were used as a sham group. The modified Morris water maze (mMWM), modified Neurological Severity Score (mNSS), and social odor–based novelty recognition tests were performed to evaluate cognitive and sensorimotor functional recovery after ICH. All 24 animals were killed 28 days after ICH or sham procedure. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume and neurovascular and white matter remodeling.

RESULTS

Compared with the saline-treated controls, exosome-treated ICH rats showed significant improvement in the neurological function of spatial learning and motor recovery measured at 26–28 days by mMWM and starting at day 14 by mNSS (p < 0.05). Senorimotor functional improvement was measured by a social odor–based novelty recognition test (p < 0.05). Exosome treatment significantly increased newly generated endothelial cells in the hemorrhagic boundary zone, neuroblasts and mature neurons in the subventricular zone, and myelin in the striatum without altering the lesion volume.

CONCLUSIONS

MSC-derived exosomes effectively improve functional recovery after ICH, possibly by promoting endogenous angiogenesis and neurogenesis in rats after ICH. Thus, cell-free, MSC-derived exosomes may be a novel therapy for ICH.

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Aqueel H. Pabaney, Kevin A. Reinard, Max K. Kole, Donald M. Seyfried and Ghaus M. Malik

OBJECT

Treatment of brain arteriovenous malformations (bAVMs) in the elderly remains a challenge for cerebrovascular surgeons. In this study the authors reviewed the patient characteristics, treatments, angiographic results, and clinical outcomes in 28 patients over 65 years of age who were treated at Henry Ford Hospital between 1990 and 2014.

METHODS

The bAVM database at the authors’ institution was queried for records of elderly patients with bAVMs, and data regarding patient demographics, presenting symptoms, bAVM angioarchitecture, treatment modalities, angiographic results, clinical outcomes, and treatment complications were tabulated and analyzed.

RESULTS

There were 9 male (32%) and 19 female (68%) patients, with an average age ( ± SD) of 73.0 ± 6.95 years. The most common symptoms on presentation were hemorrhage (36%) and headaches (18%). The bAVMs were equally distributed between the supra- and infratentorial compartments. The most common Spetzler-Martin grade was II, observed in 57% of the patients. Eleven patients (39.3%) underwent resection, 4 patients (14.3%) received standalone radiation therapy, and 13 patients (46%) did not receive treatment or were managed expectantly. Four patients (14.3%) were lost to follow-up. Complete bAVM obliteration was achieved in 87% of the treated patients. None of the patients who received any form of treatment died; the overall mortality rate was 3.6%.

CONCLUSIONS

Surgical management of bAVMs in the elderly can result in complete obliteration and acceptable clinical outcomes.

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Victor Chang, Paul Hartzfeld, Marianne Langlois, Asim Mahmood and Donald Seyfried

Object

Hemicraniectomy is a commonly practiced neurosurgical intervention with a wide range of indications and clinical data supporting its use. The extensive use of this procedure directly results in more cranioplasties to repair skull defects. The complication rate for cranial repair after craniectomy seems to be higher than that of the typical elective craniotomy. This finding prompted the authors to review their experience with patients undergoing cranial repair.

Methods

The authors performed a retrospective review of 212 patients who underwent cranial repair over a 13-year period at their institution. A database tracking age, presenting diagnosis, side of surgery, length of time before cranial repair, bone graft material used, presence of a ventricular shunt, presence of a postoperative drain, and complications was created and analyzed.

Results

The overall complication rate was 16.4% (35 of 213 patients). Patients 0–39 years of age had the lowest complication rate of 8% (p = 0.028). For patients 40–59 years of age and older than 60, complication rates were 20 and 26%, respectively. Patients who originally presented with traumatic injuries had a lower rate of complications than those who did not (10 vs 20%; p = 0.049). Conversely, patients who presented with tumors had a higher complication rate than those without (38 vs 15%; p = 0.027). Patients who received autologous bone graft placement had a statistically significant lower risk of postoperative infection (4.6 vs 18.4%; p = 0.002). Patients who underwent cranioplasty with a 0–3 month interval between operations had a complication rate of 9%, 3–6 months 18.8%, and > 6 months 26%. Pairwise comparisons showed that the difference between the 0–3 month interval and the > 6-month interval was significant (p = 0.007). The difference between the 0–3 month interval and the 4–6 month interval showed a trend (p = 0.07). No difference was detected between the 4–6 month interval and > 6-month interval (p = 0.35).

Conclusions

The overall rate of complications related to cranioplasty after craniectomy is not negligible, and certain factors may be associated with increased risk. Therefore, when evaluating the need to perform a large decompressive craniectomy, the surgeon should also be aware that the patient is not only subject to the risks of the initial operation, but also the risks of subsequent cranioplasty.

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Donald Seyfried, Yuxia Han, Dunyue LU, Jieli Chen, Ali Bydon and Michael Chopp

Object. Atorvastatin, a β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor, improves neurological functional outcome, reduces cerebral cell loss, and promotes regional cellular plasticity when administered after intracerebral hemorrhage (ICH) in rats.

Methods. Autologous blood was stereotactically injected into the right striatum in rats, and atorvastatin was administered orally beginning 24 hours after ICH and continued daily for 1 week. At a dose of 2 mg/kg, atorvastatin significantly reduced the severity of neurological deficit from 2 to 4 weeks after ICH. The area of cell loss in the ipsilateral striatum was also significantly reduced in these animals. Consistent with previous study data, higher doses of atorvastatin (8 mg/kg) did not improve functional outcome or reduce the extent of injury. Histochemical stains for markers of synaptogenesis, immature neurons, and neuronal migration revealed increased labeling in the region of hemorrhage in the atorvastatin-treated rats.

Conclusions. Analysis of the data in this study indicates that atorvastatin improves neurological recovery after experimental ICH and may do so in part by increasing neuronal plasticity.

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Donald Seyfried, Jennifer Ding, Yuxia Han, Yi Li, Jieli Chen and Michael Chopp

Object

The goal of this study was to investigate whether human bone marrow stromal cells (hBMSCs) administered by intravenous injection have a beneficial effect on outcome after intracerebral hemorrhage (ICH) in rats.

Methods

An ICH was induced in 54 adult male Wistar rats by a stereotactically guided injection of autologous blood into the right striatum. Intravenous infusion of the hBMSCs (3, 5, or 8 million cells) was performed 1 day after ICH, and for each dose group there was a control group that received injections of vehicle. Neurological function, which was evaluated using the Neurological Severity Score (NSS) and the corner turn test, was tested before and at 1, 7, and 14 days after ICH. After 14 days of survival, the area of encephalomalacia was calculated and histochemical labeling was performed.

For all three groups, there were no statistical differences in either the NSS or corner turn tests after 1 day. After 7 and 14 days, however, the three groups that received the hBMSCs showed significant improvement in functional scores compared with the control group. In addition, after 14 days there was significantly more striatal tissue loss in the placebo groups compared with each of the three treatment groups. The region of injury in the treated animals demonstrated a significantly increased presence of hBMSCs, immature neurons, neuronal migration, synaptogenesis, and newly formed DNA.

Conclusions

Intravenous administration of hBMSCs significantly improves neurological function in rats subjected to ICH. This improvement in the treated animals is associated with reduced tissue loss and increased local presence of the hBMSCs, mitotic activity, immature neurons, synaptogenesis, and neuronal migration.

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Donald M. Seyfried, Yuxia Han, Dongmei Yang, Jennifer Ding, Li Hong Shen, Smita Savant-Bhonsale and Michael Chopp

Object

Previous studies demonstrated that intravascular injection of bone marrow stromal cells (BMSCs) significantly improved neurological functional recovery in a rat model of intracerebral hemorrhage (ICH). To further investigate the fate of transplanted cells, we examined the effect of male rat BMSCs administered to female rats after ICH.

Methods

Twenty-seven female Wistar rats were subjected to ICH surgery. At 24 hours after ICH, these rats were randomly divided into 3 groups and injected intravenously with 1 ml phosphate-buffered saline or 0.5 million or 1 million male rat BMSCs in phosphate-buffered saline. To evaluate the neurological functional outcome, each rat was subjected to a series of behavioral tests (modified neurological severity score and corner turn test) at 1, 7, and 14 days after ICH. The rats were anesthetized intraperitoneally and killed, and the brain tissues were processed at Day 14 after ICH. Immunohistochemistry and in situ hybridization were used to identify cell-specific markers.

Results

The male rat BMSCs significantly improved the neurological functional outcome and also significantly diminished tissue loss when intravenously transplanted into the rats after ICH. Immunoassay for bromodeoxyuridine (BrdU) and neuronal markers demonstrated a significant increase in the number of BrdU-positive cells, which indicated endogenous neurogenesis, and a significant increase in the number of cells positive for immature neuronal markers. In situ hybridization showed that more BMSCs resided around the hematoma of the rats treated with the 1-million-cell dose compared with the 0.5-million-cell–dose group. In addition, a subfraction of Y chromosome–positive cells were co-immunostained with the neuronal marker microtubule-associated protein–2 or the astrocytic marker glial fibrillary acidic protein.

Conclusions

Male rat BMSCs improve neurological outcome and increase histochemical parameters of neurogenesis when administered to female rats after ICH. This study has shown that the intravenously administered male rat BMSCs enter the brain, migrate to the perihematomal area, and express parenchymal markers.

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Donald Seyfried, Yuxia Han, Zhang Zheng, Nancy Day, Kamiar Moin, Sandra Rempel, Bonnie Sloane and Michael Chopp

✓ Lysosomal proteases, although tightly regulated under physiological conditions, are known to contribute to cell injury after various forms of tissue ischemia have occurred. Because cathepsin B is a prominent lysosomal protease found in brain parenchyma, the authors hypothesized that it may contribute to neuronal cell death after focal cerebral ischemia. The authors measured the expression and spatial distribution of cathepsin B within the ischemic brain in 43 animals by means of immunohistochemical analysis in a rat model of transient middle cerebral artery (MCA) occlusion. Cathepsin B activity was also measured within specific ischemic brain regions by using an in vitro assay (22 animals). In addition, the authors tested the therapeutic effect of preischemic intraventricular administration of stefin A, a cysteine protease inhibitor, on the volume of cerebral infarction after transient MCA occlusion (15 animals). Increased cathepsin B immunoreactivity was detected exclusively within the ischemic neurons after 2 hours of reperfusion following a 2-hour MCA occlusion. Cathepsin B immunolocalization in the ischemic region decreased by 24 hours of reperfusion, but then increased by 48 hours of reperfusion because the infarct was infiltrated by inflammatory cells. Increased immunolocalization of cathepsin B in the inflammatory cells located in the necrotic infarct core continued through 7 days of reperfusion. Cathepsin B enzymatic activity was significantly increased in the ischemic tissue at 2, 8, and 48 hours, but not at 24 hours of reperfusion after 2 hours of MCA occlusion. Continuous intraventricular infusion of stefin A, before 2 hours of MCA occlusion (15 animals), significantly reduced infarct volume compared with control animals (12 animals): the percentage of hemispheric infarct volume was 20 ± 3.9 compared with 33 ± 3.5 (standard error of the mean; p = 0.025). These data indicate that neuronal cathepsin B undergoes increased expression and activation within 2 hours of reperfusion after a 2-hour MCA occlusion and may be a mechanism contributing to neuronal cell death. Intraventricular infusion of stefin A, an inhibitor of cathepsin B, significantly reduces cerebral infarct volume in rats.

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Dongmei Yang, Yuxia Han, Jianfeng Zhang, Christopher Ding, John Anagli and Donald M. Seyfried

Object

This study investigates a potential novel application of a selective cathepsin B and L inhibitor in experimental intracerebral hemorrhage (ICH) in rats.

Methods

Forty adult male Wistar rats received an ICH by stereotactic injection of 100 μl of autologous blood or sham via needle insertion into the right striatum. The rats were treated with a selective cathepsin B and L inhibitor (CP-1) or 1% dimethyl sulfoxide sterile saline intravenously at 2 and 4 hours after injury. Modified neurological severity scores were obtained and corner turn tests were performed at 1, 4, 7, and 14 days after ICH. The rats were sacrificed at 3 and 14 days after ICH for immunohistological analysis of tissue loss, neurogenesis, angiogenesis, and apoptosis.

Results

The animals treated with CP-1 demonstrated significantly reduced apoptosis as well as tissue loss compared with controls (p < 0.05 for each). Neurological function as assessed by modified neurological severity score and corner turn tests showed improvement after CP-1 treatment at 7 and 14 days (p < 0.05). Angiogenesis and neurogenesis parameters demonstrated improvement after CP-1 treatment compared with controls (p < 0.05) at 14 days.

Conclusions

This study is the first report of treatment of ICH with a selective cathepsin B and L inhibitor. Cathepsin B and L inhibition has been shown to be beneficial after cerebral ischemia, likely because of its upstream regulation of the other prominent cysteine proteases, calpains, and caspases. While ICH may not induce a major component of ischemia, the cellular stress in the border zone may activate these proteolytic pathways. The observation that cathepsin B and L blockade is efficacious in this model is provocative for further investigation.

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Richard S. Veyna, Donald Seyfried, Don G. Burke, Chris Zimmerman, Mark Mlynarek, Victoria Nichols, Anna Marrocco, Ajith J. Thomas, Panayiotis D. Mitsias and Ghaus M. Malik

Object. Vasospasm remains a significant source of neurological morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH), despite advances in current medical, surgical, and endovascular therapies. Magnesium sulfate therapy has been demonstrated to be both safe and effective in preventing neurological complications in obstetrical patients with eclampsia. Evidence obtained using experimental models of brain injury, cerebral ischemia, and SAH indicate that Mg may also have a role as a neuroprotective agent. The authors hypothesize that MgSO4 therapy is safe, feasible, and has a beneficial effect on vasospasm and, ultimately, on neurological outcome following aneurysmal SAH.

Methods. A prospective randomized single-blind clinical trial of high-dose MgSO4 therapy following aneurysmal SAH (Hunt and Hess Grades II–IV) was performed in 40 patients, who were enrolled within 72 hours following SAH and given intravenous MgSO4 or control solution for 10 days. Serum Mg++ levels were maintained in the 4 to 5.5 mg/dl range throughout the treatment period. Clinical management principles were the same between groups (including early use of surgery or endovascular treatment, followed by aggressive vasospasm prophylaxis and treatment). Daily transcranial Doppler (TCD) ultrasonographic recordings were obtained, and clinical outcomes were measured using the Glasgow Outcome Scale (GOS). The patients' GOS scores and the TCD recordings were analyzed using the independent t-test.

Forty patients were enrolled in the study: 20 (15 female and five male patients) received treatment and 20 (11 female and nine male patients) comprised a control group. The mean ages of the patients in these groups were 46 and 51, respectively, and the mean clinical Hunt and Hess grades were 2.6 ± 0.68 in the MgSO4 treatment group and 2.3 ± 0.73 in the control group (mean ± standard deviation [SD], p = 0.87). Fisher grades were similar in both groups. Mean middle cerebral artery velocities were 93 ± 27 cm/second in MgSO4-treated patients and 102 ± 34 cm/second in the control group (mean ± SD, p = 0.41). Symptomatic vasospasm, confirmed by angiography, occurred in six of 20 patients receiving MgSO4 and in five of 16 patients receiving placebo. Mean GOS scores were 3.8 ± 1.6 and 3.6 ± 1.5 (mean ± SD, p = 0.74) in the treatment and control groups, respectively. Significant adverse effects from treatment with MgSO4 did not occur.

Conclusions. Administration of high-dose MgSO4 following aneurysmal SAH is safe, and steady Mg++ levels in the range of 4 to 5.5 mg/dl are easily maintained. This treatment does not interfere with neurological assessment, administration of anesthesia during surgery, or other aspects of clinical care. We observed a trend in which a higher percentage of patients obtained GOS scores of 4 or 5 in the group treated with MgSO4, but the trend did not reach a statistically significant level. A larger study is needed to evaluate this trend further.

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Dongmei Yang, Robert A. Knight, Yuxia Han, Kishor Karki, Jianfeng Zhang, Christopher Ding, Michael Chopp and Donald M. Seyfried

Object

Longitudinal multiparametric MR imaging and histological studies were performed on simvastatin- or atorvastatin-treated rats to evaluate vascular repair mechanisms after experimental intracerebral hemorrhage (ICH).

Methods

. Primary ICH was induced in adult Wistar rats by direct infusion of 100 μl of autologous blood into the striatal region adjacent to the subventricular zone. Atorvastatin (2 mg/kg), simvastatin (2 mg/kg), or phosphate-buffered saline was given orally at 24 hours post-ICH and continued daily for 7 days. The temporal evolution of ICH in each group was assessed by MR imaging measurements of T2, T1sat, and cerebral blood flow in brain areas corresponding to the bulk of the hemorrhage (core) and edematous border (rim). Rats were killed after the final MR imaging examination at 28 days, and histological studies were performed. A small group of sham-operated animals was also studied. Neurobehavioral testing was performed in all animals. Analysis of variance methods were used to compare results from the treatment and control groups, with significance inferred at p ≤ 0.05.

Results

. Using histological indices, animals treated with simvastatin and atorvastatin had significantly increased angiogenesis and synaptogenesis in the hematoma rim compared with the control group (p ≤ 0.05). The statin-treated animals exhibited significantly increased cerebral blood flow in the hematoma rim at 4 weeks, while blood-brain barrier permeability (T1sat) and edema (T2) in the corresponding regions were reduced. Both statin-treated groups showed significant neurological improvement from 2 weeks post-ICH onward.

Conclusions

The results of the present study demonstrate that simvastatin and atorvastatin significantly improve the recovery of rats from ICH, possibly via angiogenesis and synaptic plasticity. In addition, in vivo multiparametric MR imaging measurements over time can be effectively applied to the experimental ICH model for longitudinal assessment of the therapeutic intervention.