TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury

Since you didn't give us EXACT amounts of BDNF and how to get them. This was totally fucking useless.

Have your doctor review all this research on BDNF and DEMAND ANSWERS!

• BDNF (167 posts to April 2011)

 

BDNF also induces hippocampal long-term potentiation, which is important for memory formation [8]. Weinstein et al. found that higher peripheral BDNF levels protect the older adults against AD. By having BDNF levels higher by one standard deviation, the risk for AD or dementia was lowered by 33% 

TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury

Author links open overlay panel

, , , , ,

https://doi.org/10.1016/j.lfs.2023.122282Get rights and content

Abstract

As one of the most prevalent neurotrophic factors in the central nervous system (CNS), brain-derived neurotrophic factor (BDNF) plays a significant role in CNS injury by binding to its specific receptor Tropomyosin-related kinase receptor B (TrkB). The BDNF/TrkB signaling pathway is crucial for neuronal survival, structural changes, and plasticity. BDNF acts as an axonal growth and extension factor, a pro-survival factor, and a synaptic modulator in the CNS. BDNF also plays an important role in the maintenance and plasticity of neuronal circuits. Several studies have demonstrated the importance of BDNF in the treatment and recovery of neurodegenerative and neurotraumatic disorders. By undertaking in-depth study on the mechanism of BDNF/TrkB function, important novel therapeutic strategies for treating neuropsychiatric disorders have been discovered. In this review, we discuss the expression patterns and mechanisms of the TrkB/BDNF signaling pathway in CNS damage and introduce several intriguing small molecule TrkB receptor agonists produced over the previous several decades.

Graphical abstract

1. Download : Download high-res image (114KB)
2. Download : Download full-size image

Introduction

A few examples of the numerous CNS disorders that can result from various causes and affect people all over the world include neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), spinal cord injury (SCI), and traumatic brain injury (TBI). It is predicted that the number of persons affected by neurodegenerative diseases like Alzheimer's will rise from the current estimate of 50 million to between 100 and 130 million by the year 2050 [1,2]. The annual global incidence of traumatic brain injury is estimated to be around 70 million [3]. The development of effective treatment regimens for complex disorders, which involve neuronal loss and degeneration, is challenging due to the complexity of the central nervous system.

Neurotrophic factors are a group of biomolecules that have been originally thought to be survival factors for neurons. In addition, they have been shown to play significant roles in the development, survival, and apoptosis of central neurons [[4], [5], [6]]. As of now, there are primarily four classes of characterized neurotrophic factors in mammals: Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4/5 (NT-4/5). They share a common ancestral gene and exhibit similarities in sequence and structure, hence collectively referred to as neurotrophic factors [7].

Mature neurotrophic factors primarily function as non-covalently linked homodimers, such as NT-3/NT-3. However, some neurotrophic factors can also form heterodimers with other neurotrophic factors, for instance, known heterodimers like NT-3/BDNF and NT-4/BDNF, which play a role in neuronal protection [8]. Neurotrophic factors exert neuroprotective and reparative effects by binding to receptors on neural terminals, activating downstream intricate signaling cascades. Known receptors fall into two major categories: the first is the initially discovered p75 neurotrophin receptor (p75NTR), which exhibits similar low affinity for each neurotrophic factor [9]. The second category comprises the Trk receptor tyrosine kinase family, which has three members: TrkA, TrkB, and TrkC, [9] characterized by relatively higher affinity and ligand specificity. TrkA primarily binds with NGF and NT-3 [10]; TrkB primarily binds with BDNF, NT-3, and NT-4/5 [11]; TrkC primarily binds with NT-3 [12]. (See Table 1.)

Brain-Derived Neurotrophic Factor (BDNF) was first isolated and purified from pig brains in the 1980s [13]. Over the span of slightly more than four decades of research, BDNF has emerged as a standout in the realm of neurotrophic factors, primarily owing to its elevated expression levels within the brain and its formidable influence on synaptic plasticity [14,15]. It has become a crucial target for the treatment of central nervous system injuries. BDNF exists in two forms: the precursor form (pro-BDNF) and the mature form (mBDNF). Mature BDNF (mBDNF) is biologically active, while pro-BDNF, the inactive form of mBDNF, exerts opposite effects. They can bind to two types of downstream receptors: the p75 neurotrophin receptor (p75NTR) with low affinity and TrkB with high affinity, activating different downstream signaling pathways [16]. Active mBDNF can bind to the TrkB receptor, promoting the MAPK/ERK, Phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and PLCγ-Ca²⁺ pathway, enhancing synaptic plasticity and facilitating neuronal protection [17,18]. On the other hand, pro-BDNF does not activate TrkB but instead, after binding with p75NTR, primarily activates the NF-κB, JNK, and Rho pathways, exerting opposite effects by inducing apoptosis in sympathetic neurons, promoting cell death, and weakening synaptic transmission[[19], [20], [21]]. TrkB signaling promotes long-term potentiation (LTP), while p75NTR signaling promotes long-term depression (LTD). The regulation of neurons is related to the balance between the two receptor-ligand binding forms [22].

The mBDNF is highly expressed in the central nervous system of adults, and it predominantly binds with TrkB receptors with high affinity. Existing research supports the notion that all synaptic functions attributed to BDNF are due to the activation of TrkB receptors, not p75NTR [15]. Therefore, the BDNF-TrkB cascade signaling pathway plays a particularly important role in neuronal protection. This paper reviews its mechanism of action in central nervous system (CNS) injuries, focusing on the BDNF-TrkB signaling pathway.

Different therapeutic approaches could make use of TrkB/BDNF's neuroprotective properties. For instance, it has been demonstrated to be beneficial in the management of epilepsy [23], depression [24], AD [25], and SCI [26]. Agonist modalities targeting this target include BDNF itself, as well as antibodies [26], small molecules, and peptides [27]. Numerous direct agonist approaches using BDNF or other proteins have demonstrated substantial limits due to the challenges of exogenous protein to overcome the blood-brain barrier. Due to this, our keen interest lies in TrkB agonists with the capability to penetrate the blood-brain barrier, especially those falling under the category of small molecules. This characteristic allows them to more effectively reach the central nervous system, thereby maximizing their agonistic impact on TrkB. Recent studies have unveiled that small molecule agonists can yield effects distinct from those of BDNF. This diversity in their features renders them intriguing subjects for study, potentially leading to practical applications based on our findings.

This review delves into the expression patterns and mechanisms of action of the TrkB/BDNF signaling pathway in CNS injury. Additionally, it explores the agonistic properties of various small compounds identified thus far as TrkB receptor agonists.

More at link.