title: Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia.
abstract: Transient spinal ischemia, a complication associated with aortic cross-clamp may lead to spastic paraplegia. Once fully developed this deficit is permanent. Quantitative histopathological assessments and pharmacological studies show that the ischemic spasticity is secondary to the loss of lumbar GABA and glycinergic inhibitory interneurons. In the present study, we investigated whether human hNT neurons or committed Sprague-Dawley rat spinal neuronal precursors (SNPs) when grafted into previously ischemic spinal segments depleted of inhibitory neurons would restore local inhibitory tone and ameliorate spasticity. Rats with functionally and electrophysiologically defined spasticity that received spinal graft of hNT neurons or neuronal precursors and immunosuppressive treatment displayed a progressive recovery of motor function that correlated with the improvement of otherwise exacerbated peripheral motor response evoked by stimulation of motor cortex. In contrast, in control, medium-injected or oligodendrocyte-grafted animals no significant therapeutic effect was seen. Stereological quantification of grafted neurons revealed 1-2% survival at three months after transplantation. These surviving neurons displayed a robust axo-dendritic sprouting and expression of markers typical of mature neurons including NSE, NeuN and synaptophysin. In both treatment groups a subpopulation of grafted neurons developed GABA immunoreactivity. These data provide evidence that a region specific grafting of hNT neurons or other neuronally committed cells, which have a potential to develop inhibitory neurotransmitter phenotype, represent an effective treatment modality to modulate ischemia-induced spastic paraplegia.
authors.affiliation: Department of Anaesthesiology -- 0818, University of California, San Diego, CA 92093, USA. mmarsala@ucsd.edu
authors.forename: Martin
authors.initials: M
authors.lastname: Marsala
authors.forename: Osamu
authors.initials: O
authors.lastname: Kakinohana
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Tomori
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsala
authors.forename: Dasa
authors.initials: D
authors.lastname: Cizkova
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004525:Efferent Pathways / Q000166:cytology / Q000502:physiology; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D007395:Interneurons / Q000166:cytology / Q000378:metabolism; D008297:Male; D014411:Neoplastic Stem Cells; D009416:Nerve Regeneration / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000637:transplantation*; D010264:Paraplegia / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000503:physiopathology / Q000601:surgery*; D020760:Spinal Cord Ischemia / Q000503:physiopathology / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000379:methods*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005680:gamma-Aminobutyric Acid