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.

Disease Modifying Potential of Glatiramer Acetate in Huntington's Disease

“…Previous studies have shown improvement in motor deficits in HD transgenic mice upon BDNF administration [12, [14, [20]. Hence, we expect that longer treatment with GA in this mouse model will improve the motor deficits observed at later stages of illness.…”

“…Accordingly, BDNF is decreased in brain tissue from human HD patients [13, [17] and in HD transgenic mice [13, [18, [19]. Notably, BDNF administration to the forebrain has shown to be protective in the R6/1 and R6/2 mouse models [12, [20] and BDNF overexpression in vivo was found to rescue HD phenotypes in YAC128 mice [14]. Moreover, BDNF knockout mice display several symptoms reminiscent of HD [21].…”

Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease

“…Brain-derived neurotrophic factor (BDNF) has been shown to have protective effects on striatal neurons both in vitro (Saudou et al, 1998) and in vivo (Bemelmans et al, 1999; Kells et al, 2004; Kells et al, 2008; Giampa et al, 2013). A decrease in BDNF levels in the cortex and the striatum has been reported in HD patients (Ferrer et al, 2000; Zuccato et al, 2001; Zuccato et al, 2008) and some HD animal models (Supplemental Table.…”

Induced Pluripotent HD Monkey Stem Cells Derived Neural Cells for Drug Discovery

“…4, 11 Compared to HD-NCs, HD-NPCs have lower mHTT expression level and mild HD cellular phenotypes that may limit its application in drug discovery research because of the lack of robust outcome measurements used to determine the beneficial effect of treatments. Many in vitro platforms have been developed for drug discovery research which include HD yeast model 12 , brain slice model 13 genetically modified 293/HEK cell 14 , primary neuronal culture from transgenic rodents 15 , transgenic rodent cell line such as PC12 16 , transgenic NHP cell line 4 and NCs derived from human iPSCs. 17, 18 However, similar to HD-NPCs, robust HD cellular phenotypes are very limited in these model systems with a narrow margin for determining therapeutic effect.…”