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Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model.
Exp Neurol. 2000 Feb; 161(2):503-16.EN

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has prominent survival-promoting effects on lesioned nigrostriatal dopamine neurons, but understanding of the conditions under which functional recovery can be obtained remains to be acquired. We report here the time course of nigrostriatal axon degeneration in the partial lesion model of Parkinson's disease and the morphological and functional effects of sequential administration of GDNF in the substantia nigra (SN) and striatum during the first 5 weeks postlesion. By 1 day postlesion, the nigrostriatal axons had retracted back to the level of the caudal globus pallidus. Over the next 6 days axonal retraction progressed down to the SN, and during the following 7 weeks 74% of tyrosine hydroxylase-positive (TH(+)) and 84% of retrogradely labeled nigral neurons were lost, with a more pronounced loss in the rostral part of the SN. GDNF administration protected 70 and 72% of the nigral TH(+) and retrogradely labeled cell bodies, respectively, but did not prevent the die-back of the lesioned nigrostriatal axons. Although clear signs of sprouting were observed close to the injection site in the striatum as well as in the globus pallidus, the overall DA innervation of the striatum [as measured by [(3)H]-N-[1-(2-benzo(b)thiopenyl)cyclohexyl]piperidine-binding autoradiography] was not improved by the GDNF treatment. Moreover, the lesion-induced deficits in forelimb akinesia and drug-induced rotation were not attenuated. We conclude that functional recovery in the partial lesion model depends not only on preservation of the nigral cell bodies, but more critically on the ability of GDNF to promote significant reinnervation of the denervated striatum.

Authors+Show Affiliations

Wallenberg Neuroscience Center, Department of Physiology, Lund University, Solvegatan 17, Lund, S-223 62, Sweden. carl.rosenblad@mphy.lu.seNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10686072

Citation

Rosenblad, C, et al. "Sequential Administration of GDNF Into the Substantia Nigra and Striatum Promotes Dopamine Neuron Survival and Axonal Sprouting but Not Striatal Reinnervation or Functional Recovery in the Partial 6-OHDA Lesion Model." Experimental Neurology, vol. 161, no. 2, 2000, pp. 503-16.
Rosenblad C, Kirik D, Björklund A. Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model. Exp Neurol. 2000;161(2):503-16.
Rosenblad, C., Kirik, D., & Björklund, A. (2000). Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model. Experimental Neurology, 161(2), 503-16.
Rosenblad C, Kirik D, Björklund A. Sequential Administration of GDNF Into the Substantia Nigra and Striatum Promotes Dopamine Neuron Survival and Axonal Sprouting but Not Striatal Reinnervation or Functional Recovery in the Partial 6-OHDA Lesion Model. Exp Neurol. 2000;161(2):503-16. PubMed PMID: 10686072.
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TY - JOUR T1 - Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model. AU - Rosenblad,C, AU - Kirik,D, AU - Björklund,A, PY - 2000/2/25/pubmed PY - 2000/4/1/medline PY - 2000/2/25/entrez SP - 503 EP - 16 JF - Experimental neurology JO - Exp Neurol VL - 161 IS - 2 N2 - Glial cell line-derived neurotrophic factor (GDNF) has prominent survival-promoting effects on lesioned nigrostriatal dopamine neurons, but understanding of the conditions under which functional recovery can be obtained remains to be acquired. We report here the time course of nigrostriatal axon degeneration in the partial lesion model of Parkinson's disease and the morphological and functional effects of sequential administration of GDNF in the substantia nigra (SN) and striatum during the first 5 weeks postlesion. By 1 day postlesion, the nigrostriatal axons had retracted back to the level of the caudal globus pallidus. Over the next 6 days axonal retraction progressed down to the SN, and during the following 7 weeks 74% of tyrosine hydroxylase-positive (TH(+)) and 84% of retrogradely labeled nigral neurons were lost, with a more pronounced loss in the rostral part of the SN. GDNF administration protected 70 and 72% of the nigral TH(+) and retrogradely labeled cell bodies, respectively, but did not prevent the die-back of the lesioned nigrostriatal axons. Although clear signs of sprouting were observed close to the injection site in the striatum as well as in the globus pallidus, the overall DA innervation of the striatum [as measured by [(3)H]-N-[1-(2-benzo(b)thiopenyl)cyclohexyl]piperidine-binding autoradiography] was not improved by the GDNF treatment. Moreover, the lesion-induced deficits in forelimb akinesia and drug-induced rotation were not attenuated. We conclude that functional recovery in the partial lesion model depends not only on preservation of the nigral cell bodies, but more critically on the ability of GDNF to promote significant reinnervation of the denervated striatum. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/10686072/Sequential_administration_of_GDNF_into_the_substantia_nigra_and_striatum_promotes_dopamine_neuron_survival_and_axonal_sprouting_but_not_striatal_reinnervation_or_functional_recovery_in_the_partial_6_OHDA_lesion_model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(99)97296-5 DB - PRIME DP - Unbound Medicine ER -