Surgical Site Infection After Autologous Cranioplasty for Decompressive Craniectomy in Traumatic Brain Injury: A Retrospective Review of Two Level 1 Trauma Centers.

OBJECT: Surgical site infection (SSI) after cranioplasty can result in unnecessary morbidity. This analysis was designed to determine the risk factors of SSI after cranioplasty in patients who received a decompressive craniectomy with the autologous bone for traumatic brain injury (TBI). METHODS: A retrospective review was performed at two level 1 academic trauma centers for adult patients who underwent autologous cranioplasty after prior decompressive craniectomy for TBI. Demographic and procedural variables were collected and analyzed for associations with an increased incidence of surgical site infection with two-sample independent t tests and Mann Whitney U tests, and with a Bonferroni correction applied in cases of multiple comparisons. Statistical significance was reported with a P value of < 0.05. RESULTS: A total of 71 patients were identified. The mean interval from craniectomy to cranioplasty was 99 days (7-283), and 3 patients developed SSIs after cranioplasty (4.2%). Postoperative drain placement (P > 0.08) and administration of intrawound vancomycin powder (P = 0.99) were not predictive of infection risk. However, a trend was observed suggesting that administration of prophylactic preoperative IV vancomycin is associated with a reduced infection rate. CONCLUSIONS: The SSI rate after autologous cranioplasty in TBI patients is lower than previously reported for heterogeneous groups and indications, and the infection risk is comparable to other elective neurosurgical procedures. As such, the authors recommend attempting to preserve native skull and perform autologous cranioplasty in this population whenever possible.

Preoperative Radiosurgery for Resected Brain Metastases: The PROPS-BM Multicenter Cohort Study.

PURPOSE: Preoperative radiosurgery (SRS) is a feasible alternative to postoperative SRS, with potential benefits in adverse radiation effect (ARE) and leptomeningeal disease (LMD) relapse. However, previous studies are limited by small patient numbers and single-institution designs. Our aim was to evaluate preoperative SRS outcomes and prognostic factors from a large multicenter cohort (Preoperative Radiosurgery for Brain Metastases [PROPS-BM]). METHODS AND MATERIALS: Patients with brain metastases (BM) from solid cancers who had at least 1 lesion treated with preoperative SRS and underwent a planned resection were included from 5 institutions. SRS to synchronous intact BM was allowed. Radiographic meningeal disease (MD) was categorized as either nodular or classical "sugarcoating" (cLMD). RESULTS: The cohort included 242 patients with 253 index lesions. Most patients (62.4%) had a single BM, 93.7% underwent gross total resection, and 98.8% were treated with a single fraction to a median dose of 15 Gray to a median gross tumor volume of 9.9 cc. Cavity local recurrence (LR) rates at 1 and 2 years were 15% and 17.9%, respectively. Subtotal resection (STR) was a strong independent predictor of LR (hazard ratio, 9.1; P < .001). One and 2-year rates of MD were 6.1% and 7.6% and of any grade ARE were 4.7% and 6.8% , respectively. The median overall survival (OS) duration was 16.9 months and the 2-year OS rate was 38.4%. The majority of MD was cLMD (13 of 19 patients with MD; 68.4%). Of 242 patients, 10 (4.1%) experienced grade ≥3 postoperative surgical complications. CONCLUSIONS: To our knowledge, this multicenter study represents the largest cohort treated with preoperative SRS. The favorable outcomes previously demonstrated in single-institution studies, particularly the low rates of MD and ARE, are confirmed in this expanded multicenter analysis, without evidence of an excessive postoperative surgical complication risk. STR, though infrequent, is associated with significantly worse cavity LR. A randomized trial between preoperative and postoperative SRS is warranted and is currently being designed.

The Role of Stereotactic Biopsy in Brain Metastases.

Brain metastases (BrM) affect up to 20% of patients with cancer and represent an increasing portion of patients with surgical brain tumors owing to improving prognoses of cancer patients in general and in many cases even of those with brain metastases. With advances in molecular biology and targeted therapy, the indications for neurosurgical sampling and specifically stereotactic biopsy are likely to change in the future. In this review the authors address some of the scientific advances in BrM biology, the clinical rationale and range of techniques currently used to perform stereotactic biopsy, and how the advent of molecular interrogation may potentially alter the way patients with BrM are managed in the future.

Radiographic and clinical outcomes using intraoperative magnetic resonance imaging for transsphenoidal resection of pituitary adenomas.

OBJECTIVE: The utility and safety of intraoperative MRI (iMRI) for resection of pituitary adenomas is not clearly established in the context of advances in endoscopic approaches. The goal in this study was to evaluate the safety and efficacy of iMRI for pituitary adenoma resection, with endoscopic transsphenoidal (ETS) versus microscopic transsphenoidal (MTS) approaches. METHODS: Radiographic and clinical outcomes of all pituitary adenomas resected using iMRI between 2008 and 2017 at a single institution were retrospectively evaluated. RESULTS: Of 212 tumors treated, 131 (62%) underwent further resection based on iMRI findings, resulting in a significant increase in gross-total resection on postoperative MRI compared with iMRI (p = 0.0001) in both ETS and MTS groups. iMRI increased rates of gross-total resection for cavernous sinus invasion Knosp grades 1 and 2, but not in Knosp ≥ 3 across treatment groups (p < 0.0001). The extent of resection on postoperative MRI was significantly correlated with increased progression-free survival (p < 0.0001). Initial hormone remission off medical therapy was achieved in 64%, with a significantly higher rate of remission in tumors resected via the ETS approach (81%) compared with the MTS approach (55%) (p = 0.02). The rate of persistent new hormone deficit was low at 8%, including a 2.8% rate of permanent diabetes insipidus, and 45% of patients had improvement in preoperative hormone deficit following surgery. Serious postoperative complications including CSF leaks requiring reoperation were rare at 1%, with no postoperative infections. CONCLUSIONS: These results suggest that iMRI is a safe and effective method of increasing the extent of resection for pituitary adenomas while preserving hormone function. When paired with the endoscope, iMRI may offer the ability to tailor more aggressive removal of tumors while optimizing pituitary function, resulting in high rates of secretory hormone remission. Secretory tumors and adenomas with Knosp grade < 3 cavernous sinus invasion may benefit most from the use of iMRI.

Clinical Outcomes in Patients with Renal Cell Carcinoma Metastases to the Choroid Plexus.

OBJECTIVE: Intraventricular metastatic brain tumors account for a small, but challenging, fraction of metastatic brain tumors (0.9%-4.5%). Metastases from renal cell carcinoma (RCC) account for a large portion of these intraventricular tumors. Although patient outcomes have been assumed to be poor, these have not been reported in a modern series with a multimodality treatment paradigm of radiotherapy (RT), resection, and cerebrospinal fluid (CSF) diversion. We have presented the first case series of patients with intraventricular metastatic tumors from RCC. METHODS: We performed a single-institution retrospective review of patients with intraventricular RCC metastases treated from January 2003 to January 2019. Volumetric analysis was used to delineate the tumor size and the Kaplan-Meier method to evaluate the survival data. RESULTS: A total of 22 intraventricular RCC metastases were identified in 19 patients with 61.3 patient-years of follow-up. The median patient age was 64 years, and the median tumor volume was 2.2 cm3. Overall, 19 metastases had been treated initially with RT. Of these, 16 had received stereotactic body RT and 3 had received whole brain RT. Three tumors were surgically excised and had received adjuvant stereotactic body RT in the upfront setting. Although 5 patients had presented with obstructive hydrocephalus, none had required CSF diversion. After treatment, 5 metastases had progressed, resulting in 1- and 3-year progression-free survival rates of 81.6% and 68%, respectively. The median overall survival was 2.8 years, with 1- and 5-year overall survival rates of 76.7% and 28.3%, respectively. Leptomeningeal carcinomatosis was not observed. CONCLUSIONS: Despite the relatively limited overall survival for this population with metastatic cancer, comparable to contemporary parenchymal brain metastasis cohorts, reasonable local central nervous system control was achieved in most patients using a paradigm of focal RT and resection, where indicated. Finally, CSF diversion was not required even in patients presenting with hydrocephalus.

Minimally Invasive Endoscopic Aspiration of a Spinal Epidural Dermoid Cyst Extending From T10 to the Sacrum: 2-Dimensional Operative Video.

Dermoid cysts are space-occupying tumors that can occur anywhere in the neuroaxis. Although categorized as benign lesions, they can compromise normal structures, causing neurological function loss, and have a tendency to recur often requiring repeated surgical resections. We illustrate the case of an extensive epidural dermoid cyst in a 22-yr-old woman who presented with progressive loss of neurological motor function in her lower extremities as well as bowel and bladder incontinence. The tumor extended from T10 to the sacrum, and a conventional operation would have entailed serial laminectomies that would cross the thoracolumbar and lumbosacral junctions, possibly requiring an instrumented fusion. Given the fact that operation would have carried significant morbidity, especially with the high likelihood of symptomatic tumoral recurrence, we consulted with our urology colleagues to find a minimally invasive way of reducing the tumor burden and decompressing the neural elements. The patient was taken to the operating room and a limited open lumbosacral durotomy was performed. A flexible cystoscope was then passed in the epidural space and used to suction the tumor. Postoperative imaging showed adequate resection, and the patient recovered neurological function completely. She had mini-mal recurrence at 3 yr and remained asymptomatic. This technical video note showcases the potential for use of endoscopy for spine tumors that have an amenable consistency, even in highly eloquent areas such as the conus medullaris. It also serves to highlight the benefits of interdisciplinary cooperation when treating complex disease. This case report was written in compliance with our institutional ethical review board. Institutional Review Board (IRB) approval and patient consent was waived in light of the retrospective and deidentified nature of the data presented in accordance with the University of Texas SouthWestern IRB. Patient consent was waived for writing this manuscript in light of the retrospective and deidentified nature of the data presented in accordance with our institutional IRB.

Retrieval of an Intracranially Migrated Dental Injection Needle Through the Foramen Ovale: 2-Dimensional Operative Video.

Dental injection needle migration is a rare complication of orthodontal procedures. When these needles fracture, they typically dislodge into the cervical space or the facial musculature. Migration into the cranial vault is difficult because of the obstacle created by the skull base. We report a rare case of intracranial migration of an anesthetic injection needle through the foramen ovale. A 59-yr-old man underwent the extraction of a right maxillary molar. The distal end of a 25-gauge injection needle broke into his pterygoid musculature, causing him pain while chewing. Vascular imaging obtained after a computed tomography scan of his face showed that the needle had migrated, potentially because of his efforts of mastication, and had traversed the foramen ovale into the middle cranial fossa. The patient started experiencing intermittent right facial numbness, likely due to compression or injury to the right trigeminal nerve. Our oral and maxillofacial colleagues did not believe that the needle could be retrieved from its facial end. The patient elected to undergo the recovery of the needle through a craniotomy given the fact that the object was contaminated and because he was becoming increasingly symptomatic. A right pterional craniotomy was planned. Extradural dissection was performed until the dura going into the foramen ovale was revealed. We could feel the metallic needle under the dural sheath of the trigeminal nerve. The dura was opened sharply directly over the needle. We then proceeded to mobilize the needle into the face, and then pulled it out completely through the craniotomy to avoid injury to the temporal lobe. The patient recovered well and was asymptomatic at the time of discharge. This case report was written in compliance with our institutional ethical review board. Institutional review board (IRB) approval and patient consent were waived in light of the retrospective and deidentified nature of the data presented in accordance with the University of Texas Southwestern (UTSW) IRB.

Intracranial anaplastic hemangiopericytoma presenting with simultaneous extra-cranial metastases: A case report and review of the literature.

BACKGROUND: Intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare mesenchymal tumor with a propensity to recur and metastasize extracranially years after treatment. Accordingly, there are no reported cases of a patient presenting with a simultaneous intracranial primary and extracranial metastases. We present the case of a patient presenting with an intracranial SFT/HPC and simultaneous liver metastases and propose a treatment paradigm. CASE DESCRIPTION: A 74-year-old male smoker presented with confusion. An MRI of the brain revealed a heterogeneously enhancing left frontal extra-axial mass. Systemic workup revealed multiple small liver lesions concerning for metastases. The patient underwent gross total resection (GTR) of the intracranial lesion with adjuvant CyberKnife stereotactic radiotherapy to the resection cavity. Pathology was consistent with a WHO Grade III SFT/HPC (previously known as anaplastic HPC). The liver lesions were biopsied and confirmed to be metastases. They were subsequently treated with stereotactic body radiation therapy, temozolomide, and bevacizumab. Eighteen months postoperatively, the patient is alive with no evidence of intracranial malignancy and regression of the hepatic lesions. CONCLUSION: Several studies support GTR and adjuvant radiotherapy to treat intracranial SFT/HPC. The role of adjuvant chemotherapy is less clear. Metastatic disease is typically detected several years after the initial diagnosis, and there is no consensus regarding the optimal treatment strategy. We propose that the rare presentation of intracranial SFT/HPC with simultaneous extracranial metastases should be treated in a multidisciplinary fashion with surgical resection, adjuvant radiotherapy, and chemotherapy.

Stem cell injections for axial back pain: a systematic review of associated risks and complications with a case illustration of diffuse hyperplastic gliosis resulting in cauda equina syndrome.

OBJECTIVE: Axial low-back pain is a disease of epidemic proportions that exerts a heavy global toll on the active workforce and results in more than half a trillion dollars in annual costs. Stem cell injections are being increasingly advertised as a restorative solution for various degenerative diseases and are becoming more affordable and attainable by the public. There have been multiple reports in the media of these injections being easily available abroad outside of clinical trials, but scientific evidence supporting them remains scarce. The authors present a case of a serious complication after a stem cell injection for back pain and provide a systematic review of the literature of the efficacy of this treatment as well as the associated risks and complications. METHODS: A systematic review of the literature was performed using the PubMed, Google Scholar, and Scopus online electronic databases to identify articles reporting stem cell injections for axial back pain in accordance with the PRISMA guidelines. The primary focus was on outcomes and complications. A case of glial hyperplasia of the roots of the cauda equina directly related to stem cell injections performed abroad is also reported. RESULTS: The authors identified 14 publications (including a total of 147 patients) that met the search criteria. Three of the articles presented data for the same patient population with different durations of follow-up and were thus analyzed as a single study, reducing the total number of studies to 12. In these 12 studies, follow-up periods ranged from 6 months to 6 years, with 50% having a follow-up period of 1 year or less. Most studies reported favorable outcomes, although 36% used subjective measures. There was a tendency for pain relief to wane after 6 months to 2 years, with patients seeking a surgical solution. Only 1 study was a randomized controlled trial (RCT). CONCLUSIONS: There are still insufficient data to support stem cell injections for back pain. Additional RCTs with long-term follow-up are necessary before statements can be made regarding the efficacy and safety.

Inflammatory Reaction Secondary to Immune Checkpoint Inhibitor Therapy Mimicking a Post-Operative Brain Abscess.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of many cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma. These therapeutics increase the activity of T cells against neoplastic cells, although the immune response generated also has the potential to target normal cells, resulting in immune related adverse events (irAEs). Most irAEs occur outside of the nervous system, but cases of limbic encephalitis, hypophysitis, optic neuritis, and pseudoprogression have been reported. CASE DESCRIPTION: Here, we present a case of an intracranial irAE after neoadjuvant stereotactic radiosurgery and craniotomy for resection of a left parietal lobe metastasis. The patient presented with headache, right-sided apraxia, and a pronator drift 2 weeks after surgery. Imaging findings were suggestive of an intracranial abscess. The lack of fever, normal white blood cell count, and benign clinical appearance in the setting of combination nivolumab and ipilimumab therapy argued in favor of an irAE, however. After initiation of dexamethasone, the neurologic deficits resolved and the magnetic resonance imaging of the brain normalized over 7 weeks. CONCLUSIONS: This is the first report of an acute surgical-site irAE after stereotactic radiosurgery and craniotomy in a patient receiving nivolumab and ipilimumab. These immune-mediated responses can be treated with corticosteroids and close observation.

Retrosigmoid Craniectomy for Vestibular Schwannoma with Hearing Preservation.

Objectives To describe a retrosigmoid craniectomy, hearing-preservation approach for resection of vestibular schwannoma. Design/Setting/Participants A video of a single patient undergoing the above approach at a tertiary care skull base surgery program. Results This video demonstrates a retrosigmoid craniectomy approach for resection of an enlarging intracanalicular vestibular schwannoma in a patient with normal hearing. The video highlights the pertinent surgical anatomy and outlines in a step-by-step fashion the surgical steps. The patient obtained a gross total resection with preservation of hearing. Conclusion A retrosigmoid craniectomy approach for vestibular schwannoma offers a potentially hearing preservation approach for selected tumors. The link to the video can be found at: https://youtu.be/VM663XztRZw .

Combined Microsurgical, Endovascular, and Endoscopic Approach to the Treatment of a Giant Vertebrobasilar Aneurysm.

BACKGROUND: Dolichoectasia is defined as elongation and dilatation of a blood vessel. In the intracranial circulation, the basilar artery is affected in 80% of cases. These are challenging lesions with an aggressive natural history, and treatment carries a relatively high rate of morbidity and mortality. We describe a case of multimodal treatment including endovascular, open microsurgical, and endoscopic endonasal approach (EEA) for management. OBJECTIVE: To describe the technical nuance of the addition of the EEA for management of posterior circulation dolichoectasia. METHODS: A 44-yr-old Hispanic woman with a 2-mo history of progressive headaches, gait disturbance, and lower cranial nerve dysfunction presented with acute neurologic decline. MRI demonstrated a dolichoectatic vertebrobasilar system with a giant 4.5-cm fusiform basilar aneurysm. RESULTS: She underwent concomitant endovascular bilateral vertebral artery sacrifice with suction decompression and trapping by clip ligation distal to the lesion. Postoperatively, she developed symptomatic pontine compression. She was then taken for a transclival EEA for intra-aneurysmal thrombectomy. Thereafter, she made a significant functional recovery. CONCLUSION: The addition of endoscopic reconstruction to the treatment of a dolichoectatic basilar aneurysm is an operative nuance that can be employed in treating these highly morbid lesions. This case describing a multimodal treatment paradigm including EEA reconstruction can serve as an example for the future of treatment select cases of dolichoectasia of the vertebrobasilar complex.

Neoadjuvant Stereotactic Radiosurgery Before Surgical Resection of Cerebral Metastases.

OBJECTIVE: Stereotactic radiosurgery (SRS) has redefined the treatment paradigm for cerebral metastases. The benefits of SRS after surgical resection of a metastatic brain tumor have been well-defined. However, it is unclear whether preoperative SRS can improve the outcomes in select patients. The present study examined the safety and efficacy of preoperative neoadjuvant SRS (NaSRS) for the treatment of cerebral metastases. METHODS: We performed a retrospective review of 12 patients treated at The University of Texas Southwestern Medical Center. All patients underwent NaSRS, followed by surgical resection of a cerebral metastasis, from 2011 to 2015. Recurrence and overall survival were characterized using Kaplan-Meier and log-rank analyses. RESULTS: The mean age was 57.5 years (range, 39-69). The median follow-up period was 13 months (range, 1-22.6). The median maximum tumor diameter was 3.66 cm (range, 2.19-4.85). The 6- and 12-month local control rates were 81.8% and 49.1%, respectively. The distant disease control rates were 72.7% and 14.5% at 6 and 12 months, respectively. Overall survival was 83.3% and 74.1% at 6 and 12 months, respectively. Two patients developed leptomeningeal disease at a mean of 11.3 months. A trend toward increased local failure was seen with larger tumor volumes and diameters (P = 0.06). CONCLUSIONS: NaSRS is a promising new approach for the treatment of select cerebral metastases that require surgical intervention. The approach is safe and effective at achieving local control. Further randomized studies with larger patient cohorts are necessary to determine whether the long-term outcomes are improved.

Intracranial Hemangiopericytomas: Recurrence, Metastasis, and Radiotherapy.

Background Intracranial hemangiopericytomas (HPCs) are characterized by high recurrence rates and extracranial metastases. Radiotherapy provides an adjunct to surgery, but the timing of therapy and the patients most likely to benefit remain unclear. Methods A retrospective review of 20 patients with HPC treated at the University of Texas Southwestern Medical Center between 1985 and 2014 was conducted. Recurrence and metastasis rates along with overall survival (OS) were characterized based on therapeutic approach and tumor pathology using Kaplan-Meier and Cox regression analyses. Results The mean age was 45.6 years (range: 19-77). Gross total resection (GTR) was achieved in 13 patients, whereas 5 patients underwent subtotal resection. Median follow-up was 91.5 months (range: 8-357). The 5-, 10-, and 15-year recurrence-free survival (RFS) rates were 61, 41, and 20%, respectively. Six patients developed metastases at an average of 113 months (range: 42-231). OS at last follow-up was 80%. Importantly, immediate postoperative adjuvant radiotherapy (IRT) did not influence RFS compared with surgery alone or OS compared with delayed radiotherapy at the time of recurrence. Conclusion HPCs have high recurrence rates necessitating close follow-up. Surgery remains an important first step, but the timing of radiotherapy for optimal control and OS remains uncertain.

Management of infectious intracranial aneurysms in the pediatric population.

INTRODUCTION: Infectious intracranial aneurysms (IIAs) account for approximately 15 % of all pediatric intracranial aneurysms. Histologically, they are pseudoaneurysms that develop in response to an inflammatory reaction within the adventitia and muscularis layers, ultimately resulting in disruption of both the internal elastic membrane and the intima. The majority of pediatric IIAs are located within the anterior circulation, and they can be multiple in 15-25 % of cases. BACKGROUND: The most common presentation for an IIA is intracerebral and/or subarachnoid hemorrhage. In children with a known diagnosis of infective endocarditis who develop new neurological manifestations, it is imperative to exclude the existence of an IIA. The natural history of untreated infectious aneurysms is ominous; they demonstrate a high incidence of spontaneous rupture. High clinical suspicion, prompt diagnosis, and adequate treatment are of paramount importance to prevent devastating neurological consequences. DISCUSSION: The prompt initiation of intravenous broad-spectrum antibiotics represents the mainstay of treatment. Three questions should guide the management of pediatric patients with IIAs: (a) aneurysm rupture status, (b) the presence of intraparenchymal hemorrhage or elevated intracranial pressure, and (c) relationship of the parent vessel to eloquent brain tissue. Those three questions should orient the treating physician into either antibiotic therapy alone or in combination with microsurgical or endovascular interventions. This review discusses important aspects of the epidemiology, the diagnosis, and the management of IIAs in the pediatric population.

Microtissue engineered constructs with living axons for targeted nervous system reconstruction.

As a common feature of many neurological diseases and injury, the loss of axon pathways can have devastating effects on function. Here, we demonstrate a new strategy to restore damaged axon pathways using transplantable miniature constructs consisting of living neurons and axonal tracts internalized within hydrogel tubes. These hydrogel microconduits were developed through an iterative process to support neuronal survival and directed axon growth. The design included hollow agarose tubes providing a relatively stiff outer casing to direct constrained unidirectional outgrowth of axons through a central soft collagen matrix, with overall dimensions of 250 µm inner diameter ×500 µm outer diameter and extending up to several centimeters. The outer casing was also designed to provide structural support of neuronal/axonal cultures during transplantation of the construct. Using neuron culture conditions optimized for the microconduits, dissociated dorsal root ganglia neurons were seeded in the collagen at one end of the conduits. Over the following week, high-resolution confocal microscopy demonstrated that the neurons survived and the somata remained in a tight cluster at the original seeding site. In addition, robust outgrowth of axons from the neurons was found, with axon fascicles constrained in a longitudinal projection along the internal collagen canal and extending over 5 mm in length. Notably, this general geometry recapitulates the anatomy of axon tracts. As such, these constructs may be useful to repair damaged axon projections by providing a transplantable bridge of living axons. Moreover, the small size of the construct permits follow-on studies of minimally invasive transplantation into potentially sensitive regions of the nervous system.

A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons.

Ibuprofen is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that ibuprofen reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons. Ibuprofen activates PPARgamma in neuron-like PC12 and B104 cells. Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARgamma blocks RhoA suppression of PPARgamma agonists in PC12 cells. Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition. These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of ibuprofen. Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease.

Mechanical breaking of microtubules in axons during dynamic stretch injury underlies delayed elasticity, microtubule disassembly, and axon degeneration.

Little is known about which components of the axonal cytoskeleton might break during rapid mechanical deformation, such as occurs in traumatic brain injury. Here, we micropatterned neuronal cell cultures on silicone membranes to induce dynamic stretch exclusively of axon fascicles. After stretch, undulating distortions formed along the axons that gradually relaxed back to a straight orientation, demonstrating a delayed elastic response. Subsequently, swellings developed, leading to degeneration of almost all axons by 24 h. Stabilizing the microtubules with taxol maintained the undulating geometry after injury but greatly reduced axon degeneration. Conversely, destabilizing microtubules with nocodazole prevented undulations but greatly increased the rate of axon loss. Ultrastructural analyses of axons postinjury revealed immediate breakage and buckling of microtubules in axon undulations and progressive loss of microtubules. Collectively, these data suggest that dynamic stretch of axons induces direct mechanical failure at specific points along microtubules. This microtubule disorganization impedes normal relaxation of the axons, resulting in undulations. However, this physical damage also triggers progressive disassembly of the microtubules around the breakage points. While the disintegration of microtubules allows delayed recovery of the "normal" straight axon morphology, it comes at a great cost by interrupting axonal transport, leading to axonal swelling and degeneration.