Presentation on theme: "AMERICAN PHYSIOLOGICAL SOCIETY EDUCATION COMMITTEE Refresher Course, 2002: Recent Advances In Neuroscience Recent Advances in Spinal Cord Injury Regeneration."— Presentation transcript:
AMERICAN PHYSIOLOGICAL SOCIETY EDUCATION COMMITTEE Refresher Course, 2002: Recent Advances In Neuroscience Recent Advances in Spinal Cord Injury Regeneration and Repair Claire E. Hulsebosch, Ph.D. Program Dir., UTMB Spinal Cord Injury Program
Spinal Cord Injury Incidence: 11,000 people a year in the USA Prevalence: Between 183,000 to 230,000 in USA Gender: Males four times as often as females Age: Most frequently to those from 16 to 30 years of age Etiology: Most commonly a result of vehicular accident, usually involving alcohol
Etiology Falls Pedestrians Medical/Surgical Sports Vehicular Violence Other Unknown Total 0-30 yrs yrs yrs Age at Injury %
Spinal cord 16 years after injury. Three spinal segments are telescoped into the space of one. The center of the scar is connective tissue which is invaded by regenerating fibers from the dorsal roots. Cervical spinal cord above a complete transverse traumatic lesion showing ascending degeneration in the dorsal (posterior) columns and spinal cerebellar and spinothalamic tracts.
Left: Dorsal view of spinal cord with fracture-dislocation at the T12-L1 junction which crushed the lumbar cord. Top Right: Longitudinal section showing site of direct cord trauma and rostral and caudal hemorrhagic extension. Bottom Right: Twelve transverse sections through the cervical and thoracic cord. The third rows from the left show almost complete hemorrhagic necrosis. Hemorrhages can be seen in the grey matter in other blocks for several centimeters.
Post-traumatic syringomyelia occurs in up to 20% of all SCI patients and in a subset of these, continues to progress over time. Shown on the top left is a section from T2 stained for myelin from an injury centered on T11. The bottom left shows a higher magnification of a different section from the same syrinx demonstrating the thick astrocytic lining of the cavity (H and E stain).
Increased Life Expectancy with Spinal Cord Injury due to Improved Patient Management World War II: 3 months 1958: 3 years 1966: 20 years 1980: 21 years Current: 27 + Cause of Death: In the past-renal failure; Current- cardiac failure, pneumonia, pulmonary emboli and septicemia. Therefore, we can turn our attention to therapeutic opportunities to increase function after SCI.
Quality of Life Issues Targeted by Patients of Spinal Cord Injury 1.Bowel and bladder control 2.Pain management 3.Hand use if limited 4.Improved locomotor function Restorative treatments will be incremental; thus, both basic and clinical measures need to be refined to be able to detect the interventions that are successful.
Number of American SCI Centers Mission Connect, Texas SCI Program, U of Texas Med. Br. The Miami Project, U Miami EPVA Center, Yale CRPF Consortium CORD, U British Columbia Reeve-Irvine Center, UC Irvine Brain Institute, U Florida The SCI Project-Keck Ctr., Rutgers Spinal Cord Res. Ctr., Manitoba SCI Program, Wash U SCoBIRC, U Kentucky Kentucky SCI Research Center, U Louisville Center for Paralysis Res., Purdue Ohio State U Georgetown U MCP Hahnemann U U Toronto State Funds: FL, KY, TX, NY, NJ, CA, VA, IL, NJ, CA, VA, IL, MD, OR, CT, BC
MASCIS SPINAL IMPACTOR
Tissue Loss after SCI 1 Hour Post Injury 60 Days Post Injury
Recovery Mechanism Resolution of acute injury events Resolution of secondary injury processes Regrowth or regeneration Time after Injury Minutes to 7d 2 h to 4 wk 24 h to years Window of Opportunity for Neurological Recovery after Spinal Cord Injury
Neuropathology of Spinal Cord Injury ACUTE: Mechanical/ischemic cell damage, hemorrhage, edema, compression, loss of vascular autoreg., systemic hypotension, injury discharge SECONDARY: Ischemic cell damage, apoptosis, electrolytic shifts, [EAA]o inc., [Ca]i inc., inflammatory casade (cytokine/chemokine), lipid peroxidation, free radical production, neutrophils-lymphocytes, reactive gliosis, edema CHRONIC: Apoptosis, receptor changes, demyelination and conduction deficits, cyst formation, regeneration/sprouting of neurites for 1 mm, neural circuit changes, central sensitization, chronic pain
Key Targets of Intervention for Spinal Cord Injury PRIMARY (ACUTE): Cessation of bleeding, relief of compression, increased blood pressure SECONDARY: Rescue of cells at risk of cell death in secondary events, stop development of inhibitory barriers to regeneration (ex. reactive gliosis, proteoglycans) CHRONIC: Repair conduction deficits, create bridges to fill the gap, promote neurite growth, replace lost cells (glial, neuronal, or engineered cell lines), aggressive physical therapy, functional electrical stimulation
McDonald, J. W. and Sadowsky, C. Lancet 359: ,2002
Phospholipase A 2 O 2.-. ONOO. NO.. OH Trauma, Ischemia Glutamate release Cell membrane NMDA-receptors Membrane phospholipids Ca 2+ Activation of enzymes Lipid peroxidation Protein oxidation DNA/RNA oxidation Free Arachidonic acid COX-2 (neurons, glia, microglia endothelium) Prostaglandins + H + ONOOH + NO 2 OXIDATIVE CELL DEATH INFLAMMATION endoperoxidases eicosanoids Selective inhibition of COX-2 (NS 398) will decrease oxidative cell injury, inhibit inflammation Inhibition of glutamate receptors will block increases in [Ca] i
Metabotropic Glutamate Group I Receptor Antagonist - AIDA (0.1 nmol) Glutamate (μM) Aspartate (μM) Time After Injury (minutes)
2.4 mm RostralEpicenter2.4 mm Caudal Vehicle AIDA LY MPEP
Mills, C.D., Johnson, K.M. and Hulsebosch, C.E., J. Neurotrauma 19:23-42,2002.
COX-2 Inhibition by NS-398
VIABLE SPINAL CORD TISSUE POST-SCI RECOVERY Hains, B.C., Yucra, J.A. and Hulsebosch, C.E. J. Neurotrauma 18: , 2001.
5-HT BDNF RN46A-V1RN46A-B14 TRANSPLANTATION FOR CHRONIC PAIN: RN46A-B14/V1 CELLS TRANSPLANTATION FOR CHRONIC PAIN: RN46A-B14/V1 CELLS 150 m
CONTROL SHAM XPL RN46A-V1 XPL RN46A-B14 XPL RATE (spikes/bin) HEMISECTED TIME (sec) LT WDR HT BR PR PI o C EVOKED ACTIVITY – CUTANEOUS STIMULI Hains, B.C., Johnson, K.M., Eaton, M.J., McAdoo, D.J., Willis, W.D. and Hulsebosch, C.E. Behavior: Exp. Neurol., 171: , 2001; Electrophysiology: Neuroscience, submitted, BR PR PI o C
TREATMENT STRATEGIES FOR SPINAL CORD INJURY Problem 1)Edema, Free radical production, Activation of arachidonic acid pathway 2)High extracellular Glut & Asp, High intracellular Ca++ 3)Inflammation 4)Secondary neuronal cell death (Apoptosis) Treatment Methylprednisolone + (30 mg/kg bolus, IV over 1 hr, followed by 5, 4 mg/kg/hr for 23 hr) within 8 hrs after injury Tirilazad mesylate * - inhibits lipid peroxidation EAA receptor antagonists (NMDA, AMPA/kainate, metabotropic Glut receptors) IL-10, LIF (anti-inflammatory cytokines), COX-2 inhibitors, CM101 (antiangiogenic drug used in cancer treatment), activated T-cells* Neurotrophins (nerve/nutrition) -NGF, BDNF, NT-3, GDNF, CNTF
Problem 5)Demyelination and conduction deficits 6)Neurite growth is only 1 mm 7)Missing circuitry, missing factors 8)Chondroitin sulfate proteoglycans and glial scarring inhibit neurite growth Treatment 4-aminopyridine * -a potassium channel- blocking agent Transplant strategies of myelinating cells GM-1* -an acidic glycolipid Neurotropins (NGF, BDNF, NT-3,GDNF) Antibodies to neurite growth inhibitors (IN-1) Matrix proteins, Schwann/OE cell transplants Transplant strategies: peripheral nerve grafts to bridge the gap, fetal tissue in bloc* (clinical trial) or disassociated, Schwann cells, olfactory ensheathing (OE) cells, motor neurons, stem cells etc. Chondroitinase-ABC to dissolve proteoglycans, local irradiation/mitotic inhibitors to inhibit glial proliferation TREATMENT STRATEGIES FOR SPINAL CORD INJURY
Problem 9)Need to relearn motor tasks 10)Loss of bladder and bowel function 11)Need improved hand function 12)Chronic pain Treatment Aggressive physical therapy * Sacral reconstruction, sacral stimulation of S2, S3, S4 ventral roots* Tendon transfer, electrical stimulation of median (flexor m.) and ulnar (adductor m.) nerves* Indwelling pumps*, transplantation of cells that secrete analgesic substances* TREATMENT STRATEGIES FOR SPINAL CORD INJURY + - standard clinical treatment * - ongoing clinical trails
Conclusions Claire E. Hulsebosch, Ph.D. Program Director UTMB Spinal Cord Injury Program 1.Ongoing clinical trials in spinal cord injury treatment demonstrate improved function. 2.Thirty years ago, patients and families would be told Nothing can be done, there is no research for treatment of spinal cord injury. This is not true today. 3.More advancements are possible by continued research efforts.