title: Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington's disease.
abstract: Loss of huntingtin-mediated BDNF gene transcription has been shown to occur in HD and thus contribute to the degeneration of the striatum. Several studies have indicated that an increase in BDNF levels is associated with neuroprotection and amelioration of neurological signs in animal models of HD. In a recent study, an increase in BDNF mRNA and protein levels was recorded in mice administered recombinant BDNF peripherally. Chronic, indwelling osmotic mini-pumps containing either recombinant BDNF or saline were surgically placed in R6/2 or wild-type mice from 4 weeks of age until euthanasia. Neurological evaluation (paw clasping, rotarod performance, locomotor activity in an open field) was performed. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that BDNF- treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as brain volume, striatal atrophy, size and morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. BDNF was effective in increasing significantly the levels of activated CREB and of BDNF the striatal spiny neurons. Moreover, systemically administered BDNF increased the synthesis of BDNF as demonstrated by RT-PCR, and this might account for the beneficial effects observed in this model.
authors.affiliation: Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital at the European Center for Brain Research, Rome, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.forename: Elena
authors.initials: E
authors.lastname: Montagna
authors.forename: Clemente
authors.initials: C
authors.lastname: Dato
authors.forename: Mariarosa A B
authors.initials: MA
authors.lastname: Melone
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Fusco
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage; D045442:Rotarod Performance Test
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D048049:Extracellular Signal-Regulated MAP Kinases