The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats

Abstract

Brain-derived neurotrophic factor (BDNF) is closely linked with neuronal survival and plasticity in psychiatric disorders. In this work, we engineered degradable, injectable alginate microspheres and non-degradable, implantable poly(ethylene vinyl acetate) matrices to continuously deliver BDNF to the dorsal hippocampus of rats for two days or more than a week, respectively. The antidepressantlike behavioral effects of BDNF delivery were examined in the Porsolt forced swim test. Rats were sacrificed 10 days after surgery and tissue samples were analyzed by western blot. A small dose of BDNF delivered in a single infusion, or from a two-day sustained release alginate implant, produced antidepressant-like behavior, whereas the same dose delivered over a longer period of time to a larger tissue region did not produce antidepressant-like effects. Prolonged delivery of BDNF resulted in a dysregulation of plasticity-related functions: increased dose and duration of BDNF delivery produced increased levels of TrkB, ERK, CREB, and phosphorylated ERK, while also producing decreased phosphorylated CREB. It is evident from this work that both duration and magnitude of BDNF dosing are of critical importance in achieving functional outcome.

New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors

“…BDNF, on the other hand, does not appear to have antidepressant activities. A small, acute dose of BDNF administered to the hippocampus yielded antidepressantlike effects, but chronic administration did not (Sirianni et al 2010). In animal models, the rapid antidepressant effects of ketamine are accompanied by enhancement of hippocampal BDNF protein levels (Garcia et al 2008).…”

Comparison of the Adulthood Chronic Stress Effect on Hippocampal BDNF Signaling in Male and Female Rats

“…BDNF receptor is TrkB, and the majority of its functions are mediated through it [7]. In addition, BDNF and TrkB are involved in the stress response in hippocampal neurons [8,9]. Response to stress is associated with changes in hippocampal BDNF levels and is related to the pathophysiology of anxiety disorders [10][11][12].…”

Long-Term Course of Brain-Derived Neurotrophic Factor Serum Levels in a Patient Treated with Deep Brain Stimulation of the Lateral Habenula

“…Both antidepressant medication and electroconvulsive therapy (ECT) induce an increase in both central and peripheral BDNF levels, suggesting that the amelioration of depressive symptoms in the wake of these therapeutic regimens is at least partly modulated by BDNF [6][7][8] . Direct delivery of BDNF into the hippocampus of rats [9][10][11] and mice [12] has shown an antidepressant effect in animal models of depression; these effects in turn were blocked when a forebrain-specific knockout of the BDNF-encoding gene was performed [13] . Thus, it seems tempting to employ the serum BDNF level as an easily accessible biomarker indicating a state of affective imbalance or, more generally, stress [14,15] .…”