Neurogenic and Neurotrophic Effects of BDNF Peptides in Mouse Hippocampal Primary Neuronal Cell Cultures

Abstract

The level of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is down regulated in Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, stress, and anxiety; conversely the level of this neurotrophin is increased in autism spectrum disorders. Thus, modulating the level of BDNF can be a potential therapeutic approach for nervous system pathologies. In the present study, we designed five different tetra peptides (peptides B-1 to B-5) corresponding to different active regions of BDNF. These tetra peptides were found to be non-toxic, and they induced the expression of neuronal markers in mouse embryonic day 18 (E18) primary hippocampal neuronal cultures. Additionally, peptide B-5 induced the expression of BDNF and its receptor, TrkB, suggesting a positive feedback mechanism. The BDNF peptides induced only a moderate activation (phosphorylation at Tyr 706) of the TrkB receptor, which could be blocked by the Trk’s inhibitor, K252a. Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H2O2-treated E18 hippocampal cells. Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner. Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated.

Oroxylin A enhances memory consolidation through the brain-derived neurotrophic factor in mice

“…More interestingly, restoration of BDNF signaling rescues various symptoms in models of these diseases (Tsukahara et al, 1995;Canals et al, 2004;Blurton-Jones et al, 2009;Nagahara et al, 2009). Although BDNF itself is implicated as a potential medicine, several strategies that manipulate BDNF-TrkB signaling, including peptidomimetics (O'Leary and Hughes, 2003;Fletcher and Hughes, 2006;Cardenas-Aguayo Mdel et al, 2013) or small molecules that stimulate endogenous BDNF expression (Nibuya et al, 1995(Nibuya et al, , 1996Lauterborn et al, 2000;Kotani et al, 2006;Bollen et al, 2013) are also considered to be potential therapeutic targets. In this study, we found that mBDNF levels gradually increased from 6 h to 24 h after oroxylin A administration in the hippocampal region of normal naïve mice.…”

Alzheimer disease therapeutics: Focus on the disease and not just plaques and tangles

“…One of the most promising approaches for neural regeneration is the development of neurotrophic compounds that can provide the biochemical microenvironment conducive to successful neurogenesis and rescue of neuronal plasticity. Peptidergic neurotrophic compounds based on ciliary neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF) are among the most promising drug candidates [150-152]. A CNTF peptidergic compound was found to successfully rescue the dentate gyrus neurogenesis and rescue neuronal/synaptic plasticity in aged mice [151, 153, 154], in a 3xTg-AD transgenic mouse model of AD [26], in an AAV1-I 2NTF-CTF rat model of sporadic AD [77], and in Ts65Dn trisomic Down syndrome mouse model [155].…”

“…In all these studies the chronic treatment with CNTF peptidergic compounds showed a significant improvement in cognitive performance and no side effects were found. Similarly, the development of compounds that can modulate BDNF [150] and direct administration of BDNF showed neuroprotective effects and improvement in cognitive performance in several transgenic mouse models and in non-human primates [156]. Thus, a combination of drugs that can inhibit neurodegeneration of the AD type and drugs that can stimulate neural regeneration of the affected brain has to be the future direction to intervene and treat AD and related neurodegenerative conditions.…”

Panax notoginsenoside Rb1 ameliorates Alzheimer’s disease by upregulating brain-derived neurotrophic factor and downregulating Tau protein expression

“…Therefore, it was demonstrated that okadaic acid inhibited BDNF expression. Increased BDNF expression in the brain may improve neuronal survival (33,34), resulting in a delay in or prevention of AD progression.…”