Nicholas C. Bambakidis, Eric M. Horn, Peter Nakaji, Nicholas Theodore, Elizabeth Bless, Tammy Dellovade, Chiyuan Ma, Xukui Wang, Mark C. Preul, Stephen W. Coons, Robert F. Spetzler, and Volker K. H. Sonntag
Sonic hedgehog (Shh) is a glycoprotein molecule that upregulates the transcription factor Gli1. The Shh protein plays a critical role in the proliferation of endogenous neural precursor cells when directly injected into the spinal cord after a spinal cord injury in adult rodents. Small-molecule agonists of the hedgehog (Hh) pathway were used in an attempt to reproduce these findings through intravenous administration.
The expression of Gli1 was measured in rat spinal cord after the intravenous administration of an Hh agonist. Ten adult rats received a moderate contusion and were treated with either an Hh agonist (10 mg/kg, intravenously) or vehicle (5 rodents per group) 1 hour and 4 days after injury. The rats were killed 5 days postinjury. Tissue samples were immediately placed in fixative. Samples were immunohistochemically stained for neural precursor cells, and these cells were counted.
Systemic dosing with an Hh agonist significantly upregulated Gli1 expression in the spinal cord (p < 0.005). After spinal contusion, animals treated with the Hh agonist had significantly more nestin-positive neural precursor cells around the rim of the lesion cavity than in vehicle-treated controls (means ± SDs, 46.9 ± 12.9 vs 20.9 ± 8.3 cells/hpf, respectively, p < 0.005). There was no significant difference in the area of white matter injury between the groups.
An intravenous Hh agonist at doses that upregulate spinal cord Gli1 transcription also increases the population of neural precursor cells after spinal cord injury in adult rats. These data support previous findings based on injections of Shh protein directly into the spinal cord.
Nicholas C. Bambakidis, John Butler, Eric M. Horn, Xukui Wang, Mark C. Preul, Nicholas Theodore, Robert F. Spetzler, and Volker K. H. Sonntag
✓ The development of an acute traumatic spinal cord injury (SCI) inevitably leads to a complex cascade of ischemia and inflammation that results in significant scar tissue formation. The development of such scar tissue provides a severe impediment to neural regeneration and healing with restoration of function. A multimodal approach to treatment is required because SCIs occur with differing levels of severity and over different lengths of time. To achieve significant breakthroughs in outcomes, such approaches must combine both neuroprotective and neuroregenerative treatments. Novel techniques modulating endogenous stem cells demonstrate great promise in promoting neuroregeneration and restoring function.
Sam Safavi-Abbasi, Joseph M. Zabramski, Pushpa Deshmukh, Cassius V. Reis, Nicholas C. Bambakidis, Nicholas Theodore, Neil R. Crawford, Robert F. Spetzler, and Mark C. Preul
The authors quantitatively assessed the effects of balloon inflation as a model of tumor compression on the brainstem, cranial nerves, and clivus by measuring the working area, angle of attack, and brain shift associated with the retrosigmoid approach.
Six silicone-injected cadaveric heads were dissected bilaterally via the retrosigmoid approach. Quantitative data were generated, including key anatomical points on the skull base and brainstem. All parameters were measured before and after inflation of a balloon catheter (inflation volume 4.8 ml, diameter 20 mm) intended to mimic tumor compression.
Balloon inflation significantly shifted (p < 0.001) the brainstem and cranial nerve foramina (mean [± standard deviation] displacement of upper brainstem, 10.2 ± 3.7 mm; trigeminal nerve exit, 6.99 ± 2.38 mm; facial nerve exit, 9.52 ± 4.13 mm; and lower brainstem, 13.63 ± 8.45 mm). The area of exposure at the petroclivus was significantly greater with balloon inflation than without (change, 316.26 ± 166.75 mm2; p < 0.0001). Before and after balloon inflation, there was no significant difference in the angles of attack at the origin of the trigeminal nerve (p > 0.5).
This study adds an experimental component to the emerging field of quantitative neurosurgical anatomy. Balloon inflation can be used to model the effects of a mass lesion. The tumor simulation created “natural” retraction and an opening toward the upper clivus. The findings may be helpful in selecting a surgical approach to increase the working space for resection of certain extraaxial tumors.
Nicholas C. Bambakidis, Nicholas Theodore, Peter Nakaji, Adrian Harvey, Volker K. H. Sonntag, Mark C. Preul, and Robert H. Miller
The continuous regeneration of glial cells arising from endogenous stem cell populations in the central nervous system (CNS) occurs throughout life in mammals. In the ongoing research to apply stem cell therapy to neurological diseases, the capacity to harness the multipotential ability of endogenous stem cell populations has become apparent. Such cell populations proliferate in response to a variety of injury states in the CNS, but in the absence of a supportive microenvironment they contribute little to any significant behavioral recovery. In the authors' laboratory and elsewhere, recent research on the regenerative potential of these stem cells in disease states such as spinal cord injury has demonstrated that the cells' proliferative potential may be greatly upregulated in response to appropriate growth signals and exogenously applied trophic factors. Further understanding of the potential of such multipotent cells and the mechanisms responsible for creating a favorable microenvironment for them may lead to additional therapeutic alternatives in the setting of neurological diseases. These therapies would require no exogenous stem cell sources and thus would avoid the ethical and moral considerations regarding their use. In this review the authors provide a brief overview of the enhancement of endogenous stem cell proliferation following neurological insult.