Gene and protein analysis of brain derived neurotrophic factor expression in relation to neurological recovery induced by an enriched environment in a rat stroke model

Abstract

Although an enriched environment enhances functional recovery after ischemic stroke, the mechanism underlying this effect remains unclear. We previously reported that brain derived neurotrophic factor (BDNF) gene expression decreased in rats housed in an enriched environment for 4 weeks compared to those housed in a standard cage for the same period. To further clarify the relationship between the decrease in BDNF and functional recovery, we investigated the effects of differential 2-week housing conditions on the mRNA of BDNF and protein levels of proBDNF and mature BDNF (matBDNF). After transient occlusion of the right middle cerebral artery of male Sprague-Dawley rats, we divided the rats into two groups: (1) an enriched group housed multiply in large cages equipped with toys, and (2) a standard group housed alone in small cages without toys.Behavioral tests before and after 2-week differential housing showed better neurological recovery in the enriched group than in the standard group. Synaptophysin immunostaining demonstrated that the density of synapses in the peri-infarct area was increased in the enriched group compared to the standard group, while infarct volumes were not significantly different. Real-time reverse transcription polymerase chain reaction, Western blotting and immunostaining all revealed no significant difference between the groups. The present results suggest that functional recovery cannot be ascribed to an increase in matBDNF or a decrease in proBDNF but rather to other underlying mechanisms.

Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

“…Enhancement of BDNF production after stroke, mainly attributable to perilesional neurons but also to microglia [28], has been suggested as a brain compensatory mechanism to prevent excessive neuronal death [29]. However, several studies have concluded that BDNF is not involved in post-stroke functional recovery [30,31]. The most likely explanation for this outcome is the incapacity of BDNF to trigger appropriate neurotrophic signalling after stroke due to a pathological imbalance of TrkB receptor isoforms.…”

Exercise and Environmental Enrichment as Enablers of Task-Specific Neuroplasticity and Stroke Recovery

“…Poststroke exercise and EE also increase expression of growth-associated proteins such as growth-associated protein 43 [49], microtubule-associated protein 2 [44], and netrin (along with the associated deleted in colorectal cancer receptor) [50], as well as markers of synaptogenesis [46,51,52]. Such proteins are involved in axonal sprouting, dendritic complexity, and spine growth [4], phenomena occurring in the peri-and contralesional cortex of functionally recovered animals [14,53].…”

Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

“…A permanent BDNF decrease is found in the infarct core, while a long-lasting upregulation, proposed to be a neuroprotective mechanism, takes place in the penumbra (Ferrer et al, 2001;Madinier et al, 2013). However, other studies rejected BDNF involvement in post-stroke recovery (Hirata et al, 2011), a likely explanation being pathological downregulation of BDNF receptors. Three independent mechanisms induced by excitotoxicity act on TrkB: (i) An inversion of mRNA ratios disfavors TrkB-FL expression over TrkB-T1 (Gomes et al, 2012;Vidaurre et al, 2012); (ii) TrkB-FL cleavage by Ca 2+dependent calpain generates a truncated receptor similar to TrkB-T1 (Gomes et al, 2012;Vidaurre et al, 2012); and (iii) regulated intramembrane proteolysis (RIP) of both isoforms by metalloproteinase/c-secretase action sheds identical ectodomains acting as BDNF scavengers (Tejeda et al, 2016).…”