Society for Neuroscience San Diego 2001

1. Society for Neuroscience San Diego 2001 A Personal Summary Wise Young, Ph.D., M.D.

2. Major Impressions • Everybody and their uncles are doing gene chips with their little lists of genes • Nuclear transcription factors that control differentiation are hot (too hot) • Therapeutic vaccines are proliferating • Very few or now studies are assessing treatments of chronic spinal cord injury • Injury studies are becoming very popular

3. Exciting Advances • Astrocytes can produce neurons • Radial glial cells are neural stem cells • C3 blockade of Rho stimulates regeneration • AIT-082 stimulates neurotrophin & stem cells • L2 CPG stimulation improves walking efficiency • Enteric glia stimulate regeneration of spinal roots • Noxious experience reduce BBB scores • Nogo receptor blockade causes regeneration • Minocycline remarkably improves BBB scores when given 0-24 hours after spinal cord contusion

4. Astrocytes Produce Neurons • Stem cells in the SVZ are probably astrocytes • Alvarez-Buylla, et al. reported that subventricular zone (SVZ) stem cells are astrocytes that give rise to neurons. • They used ARA-C drip to stop cell proliferation of stem cells. When the ARA-C stopped, production of neurons restarted. Astrocyte-like cells adjacent to ventricular ependymal cells generated cells that became neurons • GFAP-promoter linked Avian virus receptor expression transgenic mouse allowed specific labelling of astrocytes. The labeled cells started as astrocytes and then produced neurons in the olfactory bulb and the hippocampus.

5. Radial Glial Stem Cells • Noctor, et al. at Columbia • retrovirus infected radial glial cells transform to become adult neurons that show all the characteristics of neurons • In avian studies, radial glial cells are known to produce neurons • This is the first clear demonstration of this phenomenon in mouse brains

6. C3 Blockade of Rho • McKerracher, et al. reported • C3 (a bacterial toxin which binds Rho) stimulates functional improvement in rats with dorsal over-hemisections, showing significant BBB score improvements • Now they report the first evidence of regeneration in the C3 treated animals. • They also report use of novel recombinant C3 molecules that penetrate the blood brain barrier in animals, suggesting that these new drugs can be used orally or systemically.

7. L2 CPG Stimulation • CPG Stimulation in humans • Background. Many studies have shown that the central pattern generator exists in animals. Their presence in humans was theorized but never shown. • Milan Dimitrijevic showed data from 15 patients indicating that high-voltage (10-15V), 30 Hz stimulation of L2 causes activity changes that indicate locomotor function. Patients that receive this stimulation can walk further. • Richard Hermann at Good Sam at Arizona showed that such stimulation significantly reduces the metablic energy and fatigue required for walking in people with spinal cord injury, suggesting that the CPG stimulation results in more efficient activation of anti-gravity muscles.

8. AIT-082 Mechanisms • AIT-082 is being tested in clinical trials of Alzheimer’s disease and spinal cord injury. Several studies provide clues of mechanisms: • Brain neurotrophin levels increased by 100-200% in rats that had AIT-082 in their drinking water. • Stem cell proliferation assessed by BRDU labeling suggest that a 20% increase in active stem cells in the brain and spinal cord • AIT-082 prevents sensory loss in diabetic rats • AIT-082 does not bind purinergic receptors. • Non-purinergic drugs are neuroprotective and neurotrophic by promoting protein phosphorylation and not by increasing ATP levels in brain

9. Enteric Glia • Enteric glial cells • Are present in myenteric plexi located in intestinal muscle and submucosa layers • are distinct from Schwann cells and can ensheath groups of axons • migrate in CNS and do not stimulate inflammatory reaction in astrocytes • promote dorsal root ingrowth into spinal cord when transplanted to cord after dorsal root lesions • represent an accessible population of glial cells that can be transplanted to the spinal cord

10. Noxious Stimuli and BBB • Jim Grau’s laboratory at Texas A & M • Showed that training rats with 20-minute per day conditional noxious electrical stimulation of the tail can produce long-lasting behavioral effects, lowered thresholds for withdrawal of foot • Even a few hours of training can produce long-lasting deleterious effects on locomotor performance by BBB scores after contusion injuries of the spinal cord

11. Nogo Receptor Blockade • Stephen Strittmatter laboratory at Yale: • Used fragments of the 66-amino acid active domain of Nogo to bind and block the Nogo receptor • They showed that blockade of the Nogo receptor allowed significant regeneration of corticospinal tract through a spinal cord crush lesion • Functional data is still not yet available • Pictures of the regenerating axons indicate that they are scattered over both ventral and dorsal areas of the spinal cord below the injury site.

12. Minocycline • Minocyline is neuroprotective • Kiaei, et al from Cornell University showed that minocycline protects PC12 cells against NGF withdrawal and ischemia while Lin, et al. showed that minocyline attenuates bilirubin neurotoxicity • Festoff, et al. from Kansas showed that minocycline at 10 minutes, 6 hours, and 24 hours after spinal cord contusion, remarkably improved locomotor BBB scores by 3-4 points. • Ulrich, et al. from Alberta showed that minocyline inhibits pro-inflammatory cytokines in thiamine-deficient brains while Gulam, et al. showed that minocyline reduces microglial activation. • Zhang, et al. from Wisconsin showed that minocycline promoted survival of transplanted neural progenitor cells • He, et al. from Baylor showed that minocycline protected striatal cells against 6-OH-DOPA. Likewise Wu, et al. from Columbia showed that minocycline protects against MPTP but Yang, et al. from Cornell showed that minocyline aggravates MPTP damage. • Denovan-Wright from Dalhousie reports beneficial effects of minocycline in two patients with Huntington’s chorea.

13. Summary • These are only a few of many exciting studies that were presented at the Society for Neuroscience • Treatments. Several new therapies are promising, i.e. minocycline, C3 blockade of Rho, Nogo receptor blockers, and AIT-082. • Stem cells. Stem cells are glia and that they are more flexible that we had previously thought and we have more sources of cells for transplantation than before. • CPG stimulation improves walking in people with spinal cord injury. Noxious stimulus-condition can severely impair locomotor function in animals.