Protection of Striatal and Nigral neurons by Trophic and Antioxidant Mechanisms. A study on in vitro and in vivo brain insult models and neural transplants

Abstract

This thesis explored the protective effects of growth factors and antioxidants on striatal and nigral neurons in in vitro and in vivo brain insult models and neural transplants. Five different growth factors were examined for their survival-promoting effects on cultured striatal neurons: basic fibroblast growth factor (bFGF), truncated insulin-like growth factor-1 (tIGF-1), platelet derived growth factor (PDGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Dopamine and cyclic AMP regulated phosphoprotein with a molecular weight of 32 kilodaltons (DARPP-32) was employed as a specific marker for striatal projection neurons. All the growth factors enhanced the survival of DARPP-32 positive neurons under serum-free culture conditions. All but bFGF promoted the in vitro morphological development of DARPP-32 positive cells. In addition to the trophic effects under basal conditions, all the factors except for PDGF exhibited neuroprotective effects in cultures exposed to an excitatory amino acid N-methyl-D-aspartate. Moreover, BDNF and NT-3 protected against hypoglycemic injury. Antioxidant compounds. specifically the lazaroid U-83836E and the spin-trapping agent a-phenyl-tert-butyl nitrone (PBN), prevented neuronal damage induced by the in vitro insults above. Systemic treatment with PBN protected striatal neurons against degeneration induced by intrastriatal injections of the excitotoxin quinolinic acid. A similar treatment did not significantly prevent neuronal damage produced by the mitochondrial toxin 3-nitropropionic acid. The lesion-induced deficits in behavioral texts, such as drug-induced circling and skilled forelimb use, corresponded well to the extent of degeneration. Treatment of striatal donor tissue with PBN failed to promote the survival of DARPP-32 positive neurons grafted in rats with a unilateral excitotoxic lesion of the striatum. Nonetheless, the findings that the number of surviving DARPP-32-positive neurons in the graft highly correlates with the graft-induced recovery of deficits in a paw-reaching test should justify further efforts to promote the yield of graft DARPP-32-positive neurons. On the other hand, lazaroids, U-74389G and U-83836E, enhanced the survival of DA neurons transplanted in rats with a unilateral nigrostriatal lesion. Transgenic DA cells that overexpress Cu/Zn-superoxide dismutase were found to survive intrastriatal transplantation better than non-transgenic neurons. Enhanced survival of grafted DA cells correlated with more extensive functional recovery in an amphetamine-induced rotation test. In conclusion. the growth factors and the antioxidants promote the survival of striatal and nigral neurons under various conditions detrimental to cell survival, The results warrant further investigations into the possible utility of these factors in neurodegenerative diseases and clinical neural transplantation.

• author: Nakao, Naoyuki
• supervisor: [unknown] [unknown]
• opponent: Prof Zimmer, Stephen, Odense University, Denmark
• publishing date: 1996
• type: Thesis
• publication status: published
• subject: Neurosciences
• keywords: lazaroids, NT-3, BDNF, PDGF, IGF, FGF, dopamine, DARPP-32, cell culture, hypoglycemia, ischemia, oxygen free radicals, neural transplantation. excitotoxicity, Huntington's disease, Parkinson's disease, a-phenyl-tert-butyl nitrone, N-methyl-D-aspartate, Neurology, neuropsychology, neurophysiology, Neurologi, neuropsykologi, neurofysiologi
• pages: 218 pages
• defense location: Wallenberg Neuroscience Center, May 21, 1996
• defense date: 1996-05-21 10:15:00
• external identifiers: other:ISRN: LUMEDW/MEAH-1026-SE/1-218/1996
• ISBN: 91-628-2057-5
• language: English
• LU publication?: no
• id: c169ba00-4c37-4d46-a1c7-0fa8bf196907 (old id 28785)
• date added to LUP: 2016-04-04 14:17:03
• date last changed: 2018-11-21 21:19:24