title: Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington's disease.
abstract: Huntington's disease is a neurodegenerative disorder characterized by a selective degeneration of striatal projection neurons, which deal with choreic movements. Neuroprotective therapy could be achieved with the knowledge of the specific trophic requirements of these neuronal populations. Thus, the induction of endogenous trophic response or the exogenous administration of neurotrophic factors may help to prevent or stop the progression of the illness. Excitotoxicity has been implicated in the etiology of Huntington's disease, because intrastriatal injection of glutamate receptor agonists reproduces some of the neuropathological features of this disorder. Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, glial cell line-derived neurotrophic factor (GDNF), neurturin, and their receptors in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults. Transplantation of cells genetically engineered to release neurotrophic factors in the striatum has been used to study the neuroprotective effects of neurotrophin and GDNF family members in the excitotoxic model of Huntington's disease. Neurotrophins (brain-derived neurotrophic factor [BDNF], neurotrophin-3, and neurotrophin-4) protected striatal projection neurons against quinolinic or kainic acid treatment. However, GDNF family members showed a more specific action. Neurturin only protected gamma-aminobutyric acid (GABA)/enkephalinergic neurons that project to the external segment of the globus pallidus, whereas GDNF exerts its effects on GABA/substance P positive neurons, which project to the substantia nigra pars compacta and the internal segment of the globus pallidus. In conclusion, the trophic requirements of each population of striatal projection neurons are due to a complex interaction between several neurotrophic factors, such as neurotrophins and GDNF family members, which can be modified, in different pathological conditions. Moreover, these neurotrophic factors may be able to provide selective protection for basal ganglia circuits, which are affected in striatonigral degenerative disorders, such as Huntington's disease or multisystem atrophy.
authors.affiliation: Departament de Biologia Cel.lular i Anatomia Patològica, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Barcelona, Spain. alberch@medicina.ub.es
authors.forename: J
authors.initials: J
authors.lastname: Alberch
authors.forename: E
authors.initials: E
authors.lastname: Pérez-Navarro
authors.forename: J M
authors.initials: JM
authors.lastname: Canals
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000378:metabolism / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000627:therapeutic use*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D009498:Neurotoxins / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*
chemical_list: C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017470:Receptors, Glutamate