Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

Abstract

Brain-derived neurotrophic factor (BDNF) may represent a therapeutic for chronic epilepsy, but evaluating its potential is complicated by difficulties in its delivery to the brain. Here, we describe the effects on epileptic seizures of encapsulated cell biodelivery (ECB) devices filled with genetically modified human cells engineered to release BDNF. These devices, implanted into the hippocampus of pilocarpine-treated rats, highly decreased the frequency of spontaneous seizures by more than 80%. These benefits were associated with improved cognitive performance, as epileptic rats treated with BDNF performed significantly better on a novel object recognition test. Importantly, long-term BDNF delivery did not alter normal behaviors such as general activity or sleep/wake patterns. Detailed immunohistochemical analyses revealed that the neurological benefits of BDNF were associated with several anatomical changes, including reduction in degenerating cells and normalization of hippocampal volume, neuronal counts (including parvalbumin-positive interneurons), and neurogenesis. In conclusion, the present data suggest that BDNF, when continuously released in the epileptic hippocampus, reduces the frequency of generalized seizures, improves cognitive performance, and reverts many histological alterations associated with chronic epilepsy. Thus, ECB device-mediated long-term supplementation of BDNF in the epileptic tissue may represent a valid therapeutic strategy against epilepsy and some of its co-morbidities.

Smoothened receptor signaling regulates the developmental shift of GABA polarity in rat somatosensory cortex

“…acute seizure models with PTZ versus spontaneous seizures in the pilocarpine model of chronic TLE), which are able to activate different downstream signaling cascades ( Choudhry et al, 2014 ). Moreover, other studies have found that activation of the Shh–Smo signaling pathway increases the synthesis and secretion of neurotrophic factors like nerve growth factor (NGF) and BDNF ( Bond et al, 2013 ; Chen et al, 2018 ; Delmotte et al, 2020 ; Radzikinas et al, 2011 ), which may have neuroprotective effects in TLE ( Bovolenta et al, 2010 ; Falcicchia et al, 2018 ; Paradiso et al, 2009 ). Clearly, additional studies are needed to obtain a deeper knowledge of the cellular and molecular mechanisms linking epilepsy to Shh pathway components.…”

New Tools for Epilepsy Therapy

“…ECB devices secreting neuropeptides (galanin) or neurotrophic factors (glial cell-derived neurotrophic factor, GDNF and brain-derived neurotrophic factor, BDNF) have been tested in chronic animal models of epilepsy, leading to reduction in the frequency of seizures, improvements in cognitive performance, and reversal of histological alterations associated with chronic epilepsy (Kanter-Schlifke et al, 2009 ; Nikitidou et al, 2014 ; Falcicchia et al, 2018 ). Because the ECB device approach has been already scaled-up in large animal brains and tested in humans with Alzheimer disease (Wahlberg et al, 2012 ), there is optimism on the possibility of starting soon clinical studies in epileptic patients with focal, drug-resistant epilepsy.…”

Involvement of H2S, NO and BDNF‐TrkB signalling pathway in the protective effects of simvastatin against pentylenetetrazole‐induced kindling and cognitive impairments in mice

“…12 Because of its involvement in epilepsy, brain-derived neurotrophic factor (BDNF) represents an important beneficial candidate. 13 Administration of BDNF to the injured brain may provide an anti-epileptogenic activity and reverse the functional and structural abnormalities in interneurons. 14 Additionally, Sasi et al 15 documented that BDNF can regulate the synaptic interactions that may affect cognition and memory.…”