title: Modulation of excessive neuronal activity by fibroblasts: potential use in treatment of Parkinson's disease.
abstract: OBJECTIVE
  A number of neurological disorders are marked by increased or aberrant frequency of neuronal discharge in specific parts of the brain. Administration of drugs such as antiepileptic compounds results in the depression of neuronal activity in the whole brain, with the potential for serious side-effects. In the search for additional therapies to reduce the unphysiological electrical activity of over-active brain foci, we have examined the effect of fibroblasts transplanted to areas responsible for motor dysfunction in hemi-parkinsonian rats, since bursting synchronous discharges in internal segment of globus pallidus (GPi) are thought to be partially responsible for the movement disorders of PD. Fibroblasts express gap junctions and ion channels, and so, when transplanted to brain tissue, can potentially modulate excessive electrical activity.
  
  
  METHODS
  Neonatal cortical neurons were cultured on multi-electrode arrays, and their electrical activity was evaluated before and after fibroblast seeding. Unilateral 6-hydroxydopamine (6-OHDA) lesion was carried out in Fischer rats. Lesioned or control rats were transplanted with either syngeneic dermal fibroblasts, microfine glass beads, ibotenic acid, or physiological saline, in the entopeduncular nucleus (EP). Apomorphine-induced rotational behavior and L-dopa-induced dyskinetic movements were evaluated before transplantation (baseline) and 2, 4, 8, 12, and 24 weeks following transplantation. Following behavioral experiments, rats were perfused with 4% formaldehyde in PBS for immunohistochemical study of the brain.
  
  
  RESULTS
  We demonstrate in vitro that the introduction of fibroblasts into a network of neurons does not interfere with overall functional measures of activity, while moderately altering the characteristics of synchronous neuronal discharge. In rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal dopaminergic pathway, apomorphine-induced rotations were reduced by more than 60% following ipsilateral transplantation of fibroblasts to the EP. L-Dopa-induced dyskinesia was also significantly reduced. Transplantation of inert microspheres, or chemical lesion of the same area with ibotenic acid, did not produce beneficial effects on parkinsonian symptomatology.
  
  
  CONCLUSIONS
  Fibroblast transplantation could be an alternative treatment strategy for the parkinsonian patient.
authors.affiliation: Molecular Pharmacology Department, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: John P M
authors.initials: JP
authors.lastname: Finberg
authors.forename: Zoya
authors.initials: Z
authors.lastname: Gluzman
authors.forename: Michal
authors.initials: M
authors.lastname: Reshef
authors.forename: Yelena
authors.initials: Y
authors.lastname: Loboda
authors.forename: Usama
authors.initials: U
authors.lastname: Mohsen
authors.forename: Tal
authors.initials: T
authors.lastname: Bressler-Stramer
authors.forename: Reem
authors.initials: R
authors.lastname: Miari
authors.forename: Lior
authors.initials: L
authors.lastname: Gepstein
authors.forename: Shimon
authors.initials: S
authors.lastname: Marom
authors.forename: Yair
authors.initials: Y
authors.lastname: Feld
mesh_terms: D000818:Animals; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology / Q000628:therapy*; D005347:Fibroblasts / Q000637:transplantation*; D009043:Motor Activity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D016627:Oxidopamine