- Neurological Surgery
Associate Professor - University Medical Line, Neurosurgery
Member, Stanford Cancer Institute
Honors & Awards
Journal of Neuro-Oncology Award, Congress of Neurological Surgeons, (2011)
Board Certification: American Board of Neurological Surgery, Neurological Surgery (2002)
Residency: University of Washington Dept of Surgery (1997) WA
Internship: University of Washington Dept of Surgery (1990) WA
Medical Education: University of Pennsylvania Office of the Registrar (1989) PA
BA, Case Western Reserve University, Psychology and Natural Sciences (1983)
MD, University of Pennsylvania, Medicine (1989)
Current Research and Scholarly Interests
My research focuses on screening strategies to identify and characterize cancer stem cells (CSCs) in human gliomas. We are pursuing this in several ways: 1) a novel colony-forming antibody live cell array to identify distinct CSC surface phenotypes, 2) RNAi screens to identify kinases critical for CSC tumorigenicity, 3) high throughput small molecule and chemical screens to identify compounds that selectively kill or target CSCs, and 4) identifying CSCs using the tumor specific EGFRvIII
Independent Studies (5)
- Directed Reading in Neurosurgery
NSUR 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Neurosurgery
NSUR 280 (Aut, Win, Spr, Sum)
- Graduate Research
NSUR 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
NSUR 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
NSUR 199 (Aut, Win, Spr, Sum)
- Directed Reading in Neurosurgery
Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III.
2014; 74 (4): 1238-1249
The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII- cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.
View details for DOI 10.1158/0008-5472.CAN-13-1407
View details for PubMedID 24366881
An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell Differentiation
CELL STEM CELL
2010; 6 (1): 37-47
Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.
View details for DOI 10.1016/j.stem.2009.11.002
View details for Web of Science ID 000274029700010
View details for PubMedID 20085741
Health-related quality-of-life status in Veterans with spinal disorders
QUALITY OF LIFE RESEARCH
2013; 22 (1): 45-52
To measure the impact of spinal disorders on health-related quality of life (HRQOL) among Veterans, to describe demographic patterns of Veterans with spinal disorders, and to quantify HRQOL scores as they relate to demographics, medical comorbidities, pain severity, and depressive symptoms.From 2009 to 2010, 112 lumbar and 56 cervical spinal disorder patients completed SF-12, Oswestry Disability Index, visual analog pain scale, and Beck Depression Inventory surveys. Multivariate analysis identified predictors of HRQOL, disability, and depressive symptoms.A total of 168 patients completed surveys for this study. The median age of all patients was 60. Nearly 30% of lumbar and 16% of cervical patients were aged 65 or older. Approximately 96% of patients were men. Sixty percent of patients were currently receiving or had pending disability compensation. Nearly 60% of patients were current smokers, approximately 26% reported alcoholism or intravenous drug use, and 26% self-reported post-traumatic stress disorder. The most common lumbar spine diagnoses were disk herniation (36.6%) and stenosis (34.8%), and most common cervical spine diagnoses were stenosis (50.0%) and disk herniation (23.2%). Back pain was reported by 93.8% of lumbar patients and leg pain by 83.0%. Neck pain was reported by 96.4% of cervical patients and arm pain by 69.6%. Median SF-12 physical component scores were more than two standard deviations below the US average. Ninety percent of patients had at least moderate physical disability. Sixty-four percent met criteria for depressive symptoms. Visual analog pain score was the strongest predictor of SF-12 physical (β = -1.32, P < 0.001) and mental (β = -1.63, P < 0.001) HRQOL and was the prime determinant of depressive symptoms (β = 1.52, P < 0.001) and disability index score (β = 4.39, P < 0.0001). Charlson Comorbidity Score and smoking status had no significant impact on HRQOL or disability scores. Age was negatively correlated with depressive symptoms and positively correlated with SF-12 mental component scores.Spinal disorders have a severe impact on both physical and emotional HRQOL of Veterans and are associated with severe disability and an unusually high prevalence of depressive symptoms. Therapeutic interventions should be targeted to reduce pain, which is a prime determinant of HRQOL, disability, and depressive symptoms. Given high prevalence of multiple risk factors for poor outcomes, studies of spine surgery outcomes in Veterans are needed.
View details for DOI 10.1007/s11136-012-0121-y
View details for Web of Science ID 000315279300005
View details for PubMedID 22311250
Patterns of care and survival for glioblastoma patients in the Veterans population
JOURNAL OF NEURO-ONCOLOGY
2012; 106 (3): 627-635
Survival outcomes and patterns of care for brain tumor patients in the USA Veterans population have not been previously published and the extent of variation in outcomes between Veterans and the rest of the USA is currently unknown. The Veterans healthcare administration (VA) provides comprehensive care to Veterans and their families and maintains the Veterans affairs central cancer registry (VACCR). This was a retrospective review of microscopically-confirmed, supratentorial glioblastoma multiforme in male Veterans actively followed by the VACCR; survival was analyzed and compared to a national cohort from the surveillance, epidemiology and end results program. We analyzed 1,219 Veterans with glioblastomas diagnosed between 1997 and 2006. Median survival was 6.5 months and 1, 2, and 5 years survival rates were 26.8, 5.4, and 0.5%, respectively. Patients receiving all three treatment modalities (surgical resection, radiotherapy, and chemotherapy) did best; these findings remained true among patients aged 70 and older such that these patients had an overall survival similar to those age <70. A comparable national cohort had longer median survival (9.0 months) and greater 1, 2, and 5 years survival rates (37.8, 12.8, and 4.1%) than the VA cohort. Survival and patterns of care are presented for the first time for Veterans with glioblastoma multiforme. In conclusion, we found that more aggressive therapy was associated with better survival, even among elderly Veterans and whether compared overall or by age group, VA patients showed decreased survival relative to a national cohort. We believe this potential disparity warrants further investigation.
View details for DOI 10.1007/s11060-011-0702-6
View details for Web of Science ID 000299331800020
View details for PubMedID 21881877
Pituitary Adenomas Can Appear as Hypermetabolic Lesions in 18F-FDG PET Imaging
JOURNAL OF NEUROIMAGING
2010; 20 (4): 393-396
The 2-deoxy-2-[(18) F] fluoro-D-glucose positron emission tomography (FDG-PET) scan is commonly used in detection and staging of many malignant neoplasms. However, several benign or non-neoplastic conditions avidly accumulate (18) F-FDG, causing ambiguity in interpretation of results. It is unknown whether pituitary adenomas uptake (18) F-FDG and appear positive in PET imaging. Here, we present 2 cases of benign pituitary adenoma with elevated metabolic activity in (18) F-FDG PET scan.Medical, neurologic, and psychiatric histories; physical examination findings; laboratory work up results; and pathologic and imaging studies were documented.The (18) F-FDG-PET images revealed foci of marked FDG uptake in pituitary adenomas of 2 patients.Pituitary micro- and macro-adenomas may present as hypermetabolic foci on (18) F-FDG PET scan.
View details for DOI 10.1111/j.1552-6569.2008.00347.x
View details for Web of Science ID 000282574100015
View details for PubMedID 19453834
Reversal of Preoperative Catatonic State by Surgical Resection of an Adult-onset Craniopharyngioma Case Report and Review of the Literature
COGNITIVE AND BEHAVIORAL NEUROLOGY
2009; 22 (1): 67-71
To describe a case of a rare adult-onset craniopharyngioma presenting as rapidly progressive catatonia that was reversed after surgical resection of the tumor.Profoundly depressed states of awareness classified as either catatonia or akinetic mutism have been reported in patients with hypothalamic neoplasms, but reports of improvement in consciousness level after surgical resection are rare and limited to very large tumors.Medical, neurologic, and psychiatric histories, physical examination findings, laboratory workup results, pathologic and imaging studies, and response to surgical treatment were documented.The patient showed progressive improvement in mental status and overall neurologic function after surgical treatment.The search for an etiology of a profound catatonic state should include the probability of a suprasellar/hypothalamic lesion, which in this case was owing to the rare finding of an imaging-documented adult-onset craniopharyngioma.
View details for Web of Science ID 000264702100008
View details for PubMedID 19372773
Cargo areas of pickup trucks: an avoidable mechanism for neurological injuries in children
JOURNAL OF NEUROSURGERY
2007; 106 (5): 368-371
Falls from pickup truck cargo areas represent a unique mode of injury in children and adolescents. The goal of this study was to identify the neurological spectrum of injuries resulting from children riding in the back of pickup trucks.The authors undertook a retrospective review of the University of New Mexico Hospital trauma registry of data compiled over a 7-year period. Their goal was to identify instances in which a fall or ejection from a pickup truck cargo area was the mechanism of injury. The charts of pediatric patients (< or = 16 years of age) with neurological injuries were reviewed and analyzed. Seventy-three pediatric patients with injuries related to riding in the cargo areas of trucks were identified, of which 53 children (73%) had sustained neurological injuries. Among these 53 children, 64% sustained isolated head injuries, 15% isolated spine injuries, 9.4% combined spine and head injuries, 2% combined peripheral nerve, spine, and head injuries, 4% isolated peripheral nerve injuries, and 5.6% concussive events. In 53.4% of patients with neurological injuries the results of computed tomography (CT) examination were abnormal. In 36% of patients with Glasgow Coma Scale (GCS) scores of 14 to 15 there was evidence of intracranial hemorrhage on head CT scans. Injury Severity Scores were similar in the patients who were ejected and those who fell from cargo areas, but patients who were ejected had a lower mean GCS score than those who suffered falls (GCS score 12.5 and 14.3, respectively).Falls or ejections from pickup truck cargo areas result in a relatively high incidence of traumatic head, spine, and peripheral nerve injury. Head CT scanning should therefore be considered in pediatric patients with this mechanism of injury. Cargo area occupancy poses an unacceptable risk of injury and should be avoided.
View details for Web of Science ID 000246181300009
View details for PubMedID 17566203
"Paradoxical" transtentorial herniation due to CSF drainage in the presence of a hemicraniectomy
2006; 67 (8): 1513-1514
View details for Web of Science ID 000241494800046
View details for PubMedID 17060591
Intracranial dural arteriovenous fistula causing a myelopathy
2002; 40 (9): 438-442
View details for DOI 10.1038/sj.sc3101355
View details for Web of Science ID 000177892100003
View details for PubMedID 12185604
Surface passivation of a microfluidic device to glial cell adhesion: a comparison of hydrophobic and hydrophilic SAM coatings
2002; 23 (3): 929-935
Cell adhesion in a microfluidic structure can lead to catastrophic flow problems due to the comparable size of the cell with the microfabricated device. Such issues are important in the growing research area involving the merging of biological materials and MEMS devices. We have examined the surface compatibility of uncoated and coated microfabricated glass and semiconductor surfaces under static solution (cell culture) and flow experiments (microfluidic device) using glial (astrocyte and glioblastoma) cells. Bare semiconductor and glass surfaces were most attractive to cell adhesion, promoting biofouling under both static and flow conditions. Passivation of the surfaces was performed with silane coupling agents octadecyltrimethoxysilane (OTMS) or N-(triethoxysilylpropyl)-O-polyethylene oxide urethane (TESP) on SiO2 surfaces via self-assembled monolayer (SAM) deposition. The hydrophilic TESP coating was effective at inhibiting biofouling of the microfluidic structure, allowing greater than several minutes of fluid flow. The hydrophobic OTMS coating, on the other hand, promoted cell adhesion leading to restricted flow within a few minutes. Interestingly, under cell culture conditions the TESP surface exhibited biocompatible properties for glial cell adhesion and proliferation, in contrast to the OTMS surface which resisted cell growth. These studies suggest that cell adhesion is dependent upon the time domain of the cell-surface interaction.
View details for Web of Science ID 000172640000037
View details for PubMedID 11771713
Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal
2001; 6 (5): 593-604
Somatic symptoms and aversion of opiate withdrawal, regulated by noradrenergic signaling, were attenuated in mice with a CNS-wide conditional ablation of neurotrophin-3. This occurred in conjunction with altered cAMP-mediated excitation and reduced upregulation of tyrosine hydroxylase in A6 (locus coeruleus) without loss of neurons. Transgene-derived NT-3 expressed by noradrenergic neurons of conditional mutants restored opiate withdrawal symptoms. Endogenous NT-3 expression, strikingly absent in noradrenergic neurons of postnatal and adult brain, is present in afferent sources of the dorsal medulla and is upregulated after chronic morphine exposure in noradrenergic projection areas of the ventral forebrain. NT-3 expressed by non-catecholaminergic neurons may modulate opiate withdrawal and noradrenergic signalling.
View details for Web of Science ID 000170346900014
View details for PubMedID 11526474
Magnetic source imaging and brain surgery: presurgical and intraoperative planning in 26 patients
JOURNAL OF NEUROSURGERY
2000; 92 (1): 79-90
The availability of large-array biomagnetometers has led to advances in magnetoencephalography that permit scientists and clinicians to map selected brain functions onto magnetic resonance images. This merging of technologies is termed magnetic source (MS) imaging. The present study was undertaken to assess the role of MS imaging for the guidance of presurgical planning and intraoperative neurosurgical technique used in patients with intracranial mass lesions.Twenty-six patients with intracranial mass lesions underwent a medical evaluation consisting of MS imaging, a clinical history, a neurological examination, and assessment with the Karnofsky Performance Scale. Magnetic source imaging was used to locate the somatosensory cortex in 25 patients, the visual cortex in six, and the auditory cortex in four. The distance between the lesion and the functional cortex was determined for each patient. Twenty-one patients underwent a neurosurgical procedure. As a surgical adjunct, a frameless stereotactic navigational system was used in 17 cases and a standard stereotactic apparatus in four cases. Because of the results of their MS imaging examination, two patients were not offered surgery, four underwent a stereotactic biopsy procedure, 10 were treated with a subtotal surgical resection, and seven were treated with complete surgical resection. One patient deteriorated before a procedure could be scheduled and, therefore, was not offered surgery, and two patients were offered surgery but declined. Three patients experienced surgery-related complications.Magnetic source imaging is an important noninvasive neurodiagnostic tool that provides critical information regarding the spatial relationship of a brain lesion to functional cortex. By providing this information, MS imaging facilitates a minimum-risk management strategy and helps guide operative neurosurgical technique in patients with intracranial mass lesions.
View details for Web of Science ID 000084451500012
View details for PubMedID 10616086
Revascularization and bypass procedures for cerebral aneurysms
NEUROSURGERY CLINICS OF NORTH AMERICA
1998; 9 (4): 697-?
Revascularization and bypass procedures are useful in the treatment of complex aneurysms. Extracranial to intracranial bypass grafts are used to augment the distal circulation as an adjunct to proximal vessel occlusion for aneurysm treatment. Bypass grafts are used also to ensure adequate distal circulation during aneurysm trapping procedures. Recent improvements in vascular exposures at the skull base have allowed the development of vessel replacement or interposition grafts for arteries harboring aneurysms at the skull base. Intracranial interposition grafts are used to reconstruct arteries harboring aneurysms that cannot be occluded directly using clip or coil techniques. These techniques in the treatment of cerebral aneurysms are discussed.
View details for Web of Science ID 000076697200006
View details for PubMedID 9738101
Intracranial vascular anastomosis using the microanastomotic system - Technical note
JOURNAL OF NEUROSURGERY
1998; 89 (4): 676-681
The authors describe the use of a microanastomotic device to perform intracranial end-to-end vascular anastomoses. Direct end-to-end anastomosis was performed between the superficial temporal artery and branches of the middle cerebral artery (MCA) in three patients. Two patients had moyamoya disease, with severe proximal MCA disease, and one suffered an internal carotid artery occlusion with poor collateral flow. All patients reported a history of recent ischemic symptoms. Each anastomosis was accomplished in less than 15 minutes with technically satisfactory results. Postoperative angiographic studies demonstrated patency of the bypasses in all patients.
View details for Web of Science ID 000076073000026
View details for PubMedID 9761067
Noninvasive physiologic evaluation of the aneurysm patient
NEUROSURGERY CLINICS OF NORTH AMERICA
1998; 9 (3): 463-?
Patients harboring intracranial aneurysms may experience secondary brain injury around the time of aneurysm repair, either from the repair process itself or secondary to altered cerebral vascular physiology following subarachnoid hemorrhage. Management of patients with aneurysms includes strategies to avoid or minimize secondary brain injury. Various technologies have been employed to monitor patients undergoing treatment for cerebral aneurysms to detect and treat causes of secondary ischemic damage. These methods include monitoring for cerebral ischemia and monitoring of electrophysiologic function of the brain. This article discusses noninvasive techniques which have been employed to monitor cerebral function in aneurysm patients.
View details for Web of Science ID 000074837400005
View details for PubMedID 9668180
Functional cortex and subcortical white matter located within gliomas
1996; 38 (4): 678-684
Some neurosurgeons state that intra-axial tumors may be resected with a low risk of neurological deficit if the tumor removal stays within the confines of the grossly abnormal tissue. This is thought to be so even when the lesion is presumably located in a functional area, providing that the adjacent normal-appearing cortex and subcortical white matter are not disturbed. This retrospective analysis presents evidence that this view is not always correct, because functioning motor, sensory, or language tissue can be located within a grossly obvious tumor or the surrounding infiltrated brain. Intraoperative stimulation mapping techniques identified 28 patients, ranging in age between 22 and 73 years, who showed evidence of functional tissue within the boundaries of infiltrative gliomas, as identified by correlation with computed tomography and magnetic resonance imaging scans, intraoperative ultrasound, gross visualization, and histological confirmation. Direct stimulation mapping of cortical and subcortical portions of the tumor during resections identified motor, sensory, naming, reading, or speech arrest function. Nineteen patients had new or worsened neurological deficits immediately after the operation, but after 3 months, only 6 continued to show new deficits whereas 18 showed no deficits and 2 improved. These results demonstrate that regardless of the degree of tumor infiltration, swelling, apparent necrosis, and gross distortion by the mass, functional cortex and subcortical white matter may be located within the tumor or the adjacent infiltrated brain. Therefore, to safely maximize glioma resection in these functional areas, intraoperative stimulation mapping may be used to identify functional cortical or subcortical tissue within, as well as adjacent to, the tumor, thus avoiding permanent injury.
View details for Web of Science ID A1996UA47100021
View details for PubMedID 8692384
INVIVO CHANGES OF CATECHOLAMINES IN HEMIPARKINSONIAN MONKEYS MEASURED BY MICRODIALYSIS
1990; 110 (2): 187-193
In monkeys, unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a useful model of hemiparkinsonism. To evaluate MPTP-induced neurochemical changes in vivo, brain microdialysis was employed to measure extracellular levels of dopamine and its metabolites in the neostriatum of normal and hemiparkinsonian rhesus monkeys (Macaca mulatta). The microdialysis probes were implanted bilaterally into the caudate nucleus and putamen at coordinates determined from magnetic resonance imaging. Dopamine and its metabolites were depleted in the MPTP-lesioned side versus the unlesioned side in hemiparkinsonian monkeys. Tyrosine hydroxylase immunocytochemistry revealed a complete unilateral denervation in the caudate nucleus and putamen and a total loss of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta in those monkeys. Baseline levels of amines in the neostriatum in normal monkeys were not significantly different from those in the normal (non-MPTP-treated) side in hemiparkinsonian monkeys. These data demonstrate that brain microdialysis is a valuable tool for measuring in vivo neurochemical changes in nonhuman primate brains.
View details for Web of Science ID A1990EJ27100004
View details for PubMedID 1699780
METHODOLOGY OF MICRODIALYSIS OF NEOSTRIATUM IN HEMIPARKINSONIAN NONHUMAN-PRIMATES
1990; 110 (2): 181-186
In vivo biochemical microdialysis in primate brain would greatly expand our understanding of functional neuronal systems. This work describes our efforts to establish a microdialysis system in primate brain. Seven anesthetized rhesus monkeys underwent magnetic resonance imaging (MRI) with the head fixed in a compatible stereotaxic frame. This allowed stereotaxic localization of the caudate nucleus and putamen. Guide cannulae were implanted and fixed to the skull. Microdialysis probes made from polyethylene and fused silica were inserted into the caudate and putamen through the guide cannulae and perfused at the rate of 1.3 microliters/min. The putamens were approached horizontally, while the caudate nuclei were reached via a 30 degrees-45 degrees angle from the vertical. Postdialysis MRI and histologic evaluation proved that all probes accurately arrived at the predetermined region. Our data show that MRI guided stereotaxis allows accurate placement of dialysis probes and that implantation of guide cannulae is a reliable and convenient way to perform repeated brain microdialysis procedures.
View details for Web of Science ID A1990EJ27100003
View details for PubMedID 2226698
SURVIVAL OF ADULT 5-HT NEURONS FOLLOWING INTRAOCULAR TRANSPLANTATION
1989; 484 (1-2): 257-267
The present study was undertaken to provide an improved environment in which to examine the capacity of more mature CNS tissue to survive following transplantation. Tissue containing serotonin (5-HT) neurons from nucleus raphe dorsalis of 4- and 8-week-old rats was transplanted to the anterior chamber of the eye. Baseline conditions were improved by minimizing the time of the grafting procedure and enhancing the nutrition and oxygenation of the grafting medium. Additional treatment of the grafts during the 4 weeks of in oculo development included either: (1) intermittent hyperbaric oxygen (HBO), (2) continuous hyperoxia, or (3) control. In vivo measurement revealed that all grafts decreased significantly in size, a majority of which still demonstrated a small degree of vascularization. Microscopically, a significant percentage of the grafts demonstrated 5-HT-immunoreactive (5-HT-ir) fiber outgrowth into the host irides, although 5-HT-ir cell bodies could not always be discerned. In terms of percentage of grafts with surviving 5-HT-ir fibers, the best results were seen with the grafts treated with continuous hyperoxia (3 out of 4), as compared to HBO-treated grafts (4/18) and the control group (3/24). For both the HBO-treated and control groups, slightly better results were seen with 4-week-old vs 8-week-old donor tissue. The density and the surface area covered by the 5-HT-ir fibers was not correlated with either treatment or donor age. Thus, while continuous hyperoxia or HBO treatment may have a positive effect, the enhanced baseline conditions appear to provide an environment in which to demonstrate that 5-HT neurons from 4- and 8-week-old rats possess the capacity to survive transplantation.
View details for Web of Science ID A1989U226100026
View details for PubMedID 2713686
NERVE GROWTH-FACTOR CAN INFLUENCE GROWTH OF CORTEX CEREBRI AND HIPPOCAMPUS - EVIDENCE FROM INTRAOCULAR GRAFTS
1989; 30 (3): 755-766
The effects of nerve growth factor and antiserum against nerve growth factor on cortical cholinergic projection areas in the central nervous system and cerebellum were evaluated using intraocular grafts of cortex cerebri, hippocampus and cerebellum in rat hosts receiving injections into the anterior chamber of the eye of nerve growth factor (at transplantation, 5 and 10 days after transplantation) or antiserum to nerve growth factor (every 5 days). The controls received cytochrome c or preimmune serum. Growth of grafts was followed by repeated observations directly through the cornea of the host using a stereomicroscope. Nerve growth factor-treated grafts of cortex cerebri and hippocampus grew significantly smaller as compared to the corresponding control grafts. In one experiment, growth of cytochrome c and saline-treated cortex cerebri was compared and no difference in growth was found. Growth of nerve growth factor-treated cerebellar grafts did not differ significantly from growth of cytochrome c-treated grafts. Morphological analysis using Nissl-staining, antibodies to glial acidic fibrillary protein to evaluate the degree of gliosis and antiserum to neurofilament as a neuronal marker did not reveal any marked differences between nerve growth factor- and cytochrome c-treated grafts. Cortical grafts receiving anti-nerve growth factor antiserum by injection or by immunizing host rats against nerve growth factor showed similar growth to the controls. Similarly, grafts of fetal hippocampus to rats immunized with nerve growth factor were not significantly different from grafts to host rats immunized with cytochrome c. We conclude that exogenous nerve growth factor affects the development of grafted cortex cerebri and hippocampus. The fact that these cortical areas stop growing earlier in the presence of nerve growth factor without the grafts showing evidence of disturbed glial or neuronal populations compared to control grafts indicates that nerve growth factor acts to induce overall/premature differentiation and maturation. The mechanism for this whether or not it is receptor-mediated and which cells are primarily affected by nerve growth factor is not yet known.
View details for Web of Science ID A1989AH23300017
View details for PubMedID 2549445
NGF TREATMENT PROMOTES DEVELOPMENT OF BASAL FOREBRAIN TISSUE GRAFTS IN THE ANTERIOR-CHAMBER OF THE EYE
EXPERIMENTAL BRAIN RESEARCH
1989; 74 (1): 89-98
The effects of nerve growth factor (NGF) on developing central cholinergic neurons were studied using intraocular grafts of rat fetal (E17) basal forebrain tissue. Prior to grafting, grafts were incubated in NGF or saline. Transplants were allowed to mature for six weeks, receiving weekly intraocular injections of NGF or saline. Measurements of NGF levels in oculo after one single injection showed that NGF slowly decreases in the anterior chamber fluid, and after one week, low but significant levels were still present in the eye. Following pretreatment with diisopropylfluorophosphate (DFP), the cholinergic neurons in the grafts were analyzed using three morphological markers: antibodies to cholineacetyltransferase (ChAT), antibodies to acetylcholinesterase (AChE Ab) and acetylcholinesterase histochemistry (AChE). The transplants grew well and became vascularized within the first week. The growth of the NGF-treated basal forebrain grafts was significantly enhanced as compared to the growth of the saline-treated grafts evaluated with repeated stereomicroscopical observations directly through the cornea of the ether-anaesthetized hosts. The NGF-treated grafts contained almost twice as many cholinergic neurons seen with all the cholinergic markers used, as the saline-treated grafts. However, there was no difference in cholinergic cell density between the two groups. The morphology and size of an individual cholinergic neuron was similar in the two groups. The fiber density as evaluated with AChE-immunohistochemistry did not change after NGF-treatment. The DFP-treatment did not seem to affect the AChE-immunoreactivity since an extensive fiber network was found, whereas almost no fibers were seen using conventional AChE histochemistry. We have demonstrated that in oculo transplantation of basal forebrain is a useful model for examining in vivo effects of NGF on central cholinergic function. The marked volume increase of NGF-treated grafts and the unchanged density of cholinergic cells and terminals suggests, that NGF increases the survival of not only developing cholinergic neurons, but possibly other non-cholinergic neurons and non-neuronal cells as well. These results support the notion that NGF acts as a neurotrophic factor on cholinergic and possibly non-cholinergic cells in the central nervous system.
View details for Web of Science ID A1989R780300009
View details for PubMedID 2924843