Open access peer-reviewed chapter
Abstract
The neuromodulatory effect of brain-derived neurotrophic factor (BDNF) in spinal cord injury (SCI) is a topic of significant interest. BDNF, a neurotrophic factor, plays a crucial role in promoting neuronal survival, axonal growth, and synaptic plasticity in the central nervous system. In SCI, BDNF has been shown to enhance the survival of injured neurons and stimulate axonal growth through the activation of downstream signaling pathways. Additionally, BDNF exhibits potent anti-inflammatory effects, reducing neuroinflammation and secondary damage. The timing and duration of BDNF administration are critical, with early intervention showing better outcomes. However, the optimal dosage and frequency of BDNF administration remain to be determined. Further research is needed to fully understand the potential of BDNF as a therapeutic agent for enhancing functional recovery and promoting neuroplasticity in individuals with SCI.
Keywords
- spinal cord injury
- BDNF
- neuromodulation
- orthopedics
- remodeling
1. Introduction
Spinal cord injury (SCI) is a catastrophic condition that impacts millions of people globally, causing permanent loss of motor and sensory function below the injury site, leading to a diminished quality of life [1]. Despite advancements in medical care and rehabilitation, there are no successful treatments available to promote substantial functional recovery following SCI.
Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have emerged as promising therapeutic agents for promoting functional recovery after SCI [2]. BDNF is a member of the neurotrophin family of growth factors and plays a crucial role in promoting neuronal survival, axonal growth, and synaptic plasticity in the central nervous system (CNS). In addition to its neurotrophic effects, BDNF also has potent anti-inflammatory and neuroprotective effects, making it an attractive candidate for promoting functional recovery after SCI [3] (Figure 1).
Figure 1.
Relation between BDNF and axonal regeneration (Thank you to Derin Mavi Bora for the illustration).
Several preclinical and clinical studies have demonstrated the potential of BDNF for promoting functional recovery after SCI [3, 4, 5]. These studies have shown that BDNF administration can promote axonal regeneration, improve synaptic plasticity, and reduce inflammation in animal models of SCI and in humans [4]. Despite these promising results, there are still many questions that remain unanswered regarding the optimal timing, dose, and route of administration of BDNF for SCI, as well as the long-term safety and efficacy of BDNF in humans.
In this review, we will explore the neuromodulatory effects of BDNF in SCI, including its effects on axonal regeneration, synaptic plasticity, and inflammation. We will also discuss the challenges and limitations of using BDNF for SCI, as well as future directions for research in this area. By examining the current state of knowledge on the neuromodulatory effects of BDNF in SCI, we hope to provide a comprehensive overview of this promising therapeutic approach and its potential for promoting functional recovery after SCI.
2. Axonal regeneration
Axonal regeneration is a critical process for promoting functional recovery after SCI. However, the regenerative capacity of the central nervous system (CNS) is limited, and axonal regeneration after SCI is typically minimal. BDNF has been shown to promote axonal regeneration in animal models of SCI through several mechanisms [6].
BDNF initially enhances the survival of damaged neurons and facilitates the growth of axons. The protein induces this effect by activating signaling pathways downstream, which control the expression of genes linked to axonal growth and survival. These signaling pathways involve the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, which regulate the production of growth-associated proteins and encourage the growth and survival of axons [7].
Second, BDNF promotes the migration of neural stem cells (NSCs) to the site of injury, where they can differentiate into neurons and support neuronal survival and growth [7]. The protein achieves this effect by activating downstream signaling pathways that regulate the migration and differentiation of NSCs, including the MAPK pathway and the PI3K pathway [8].
Third, BDNF promotes the formation of new synapses and the reorganization of neural circuits. The protein achieves this effect by activating downstream signaling pathways that regulate the expression of synaptic proteins and promote the formation of new synapses. These pathways include the protein kinase B (AKT) pathway and the extracellular signal-regulated kinase (ERK) pathway, which regulate the expression of synaptic proteins and promote the formation of new synapses [9].
Axonal regeneration refers to the process by which damaged or severed axons in the nervous system grow and reestablish connections with their target tissues. In the case of spinal cord injury (SCI), axonal regeneration is a critical step in promoting functional recovery as it can help restore communication between the brain and the rest of the body [6].
Axonal regeneration is a complex process that involves several steps. First, the damaged axon must form a growth cone, which is a specialized structure at the tip of the axon that guides its growth toward the target tissue. The growth cone is sensitive to guidance cues in the extracellular environment, such as extracellular matrix molecules and chemotropic factors, which help direct the axon toward its target [8].
Once the growth cone reaches its target tissue, it must form a new synapse, which is the site of communication between the axon and the target cell. Synapse formation requires the release of neurotransmitters from the axon and the activation of receptors on the target cell, leading to the transmission of signals between the two cells [8].
In the context of SCI, axonal regeneration is hindered by several factors, including the presence of inhibitory factors in the extracellular environment, the loss of trophic support from target tissues, and the formation of a glial scar, which is a dense network of astrocytes that form at the site of injury and inhibit axonal regeneration.
BDNF has been shown to promote axonal regeneration after SCI by overcoming some of these inhibitory factors and promoting the growth and guidance of damaged axons. BDNF can promote axonal regeneration by increasing the expression of growth cone proteins and chemotropic factors, reducing the expression of inhibitory factors, and enhancing the survival and growth of damaged axons [9]. By promoting axonal regeneration, BDNF can help restore communication between the brain and the rest of the body, leading to improved functional recovery after SCI [7].
3. Neuronal excitability
Neuronal excitability is a critical process for promoting functional recovery after SCI. After SCI, there is a significant decrease in neuronal excitability, which contributes to the loss of neurological function. BDNF has been shown to promote neuronal excitability in animal models of SCI through several mechanisms [10].
First, BDNF promotes the expression of ion channels and receptors that regulate neuronal excitability [11]. The protein achieves this effect by activating downstream signaling pathways that regulate the transcription and translation of ion channels and receptors, including the AKT pathway and the ERK pathway [12].
Second, BDNF modulates synaptic transmission by regulating the release of neurotransmitters and the expression of neurotransmitter receptors. The protein achieves this effect by activating downstream signaling pathways that regulate the expression and trafficking of neurotransmitter receptors [13].
Third, BDNF promotes the generation and propagation of action potentials by regulating the expression and activity of voltage-gated ion channels [13].
4. Synaptic plasticity
Synaptic plasticity is a critical process for promoting functional recovery after SCI. It is the ability of synapses to change their strength and efficacy in response to activity, which is essential for learning, memory, and adaptive behavior. After SCI, there is a significant decrease in synaptic plasticity, which contributes to the loss of neurological function. BDNF has been shown to promote synaptic plasticity in animal models of SCI through several mechanisms [14].
First, BDNF promotes the expression and trafficking of AMPA receptors, which are critical for synaptic plasticity. The protein achieves this effect by activating downstream signaling pathways that regulate the expression and trafficking of AMPA receptors, including the AKT pathway and the ERK pathway [15].
Second, BDNF promotes the formation and stabilization of dendritic spines, which are the primary sites of excitatory synaptic transmission. The protein achieves this effect by activating downstream signaling pathways that regulate the expression of cytoskeletal proteins and promote the formation and stabilization of dendritic spines [15].
Third, BDNF promotes the release of neurotransmitters and the activation of downstream signaling pathways that regulate synaptic plasticity. The protein achieves this effect by activating downstream signaling pathways that regulate the release of neurotransmitters, including the MAPK pathway and the PI3K pathway [16].
Synaptic plasticity refers to the ability of synapses, the connections between neurons in the nervous system, to change and adapt in response to experience or injury. Synaptic plasticity is a fundamental process underlying learning, memory, and recovery from injury in the nervous system.
In the context of spinal cord injury (SCI), synaptic plasticity can play a critical role in promoting functional recovery by allowing for the formation of new connections and the strengthening of existing ones. After SCI, the loss of connections between neurons can lead to a reduction in synaptic activity, which can impair motor and sensory function [14].
BDNF is a potent modulator of synaptic plasticity in the nervous system and has been shown to promote the formation of new synapses, increase the strength of existing ones, and enhance synaptic transmission after injury. BDNF can promote synaptic plasticity by increasing the release of neurotransmitters, enhancing the expression and localization of synaptic proteins, and regulating synaptic pruning and remodeling [17].
BDNF’s ability to promote synaptic plasticity after SCI makes it a promising therapeutic agent for promoting functional recovery. By enhancing synaptic plasticity, BDNF can help restore connectivity between neurons, leading to improved motor and sensory function after SCI [17].
In addition to its effects on synaptic plasticity, BDNF can also promote neuronal survival and protect against apoptosis, which can further contribute to functional recovery after SCI. By promoting neuronal survival and protecting against cell death, BDNF can help maintain the integrity of neural circuits and prevent the loss of connections between neurons.
Overall, synaptic plasticity is a critical process underlying functional recovery after SCI, and BDNF’s ability to enhance synaptic plasticity and promote neuronal survival makes it a promising therapeutic agent for promoting functional recovery in this population.
5. Neuroinflammation
Neuroinflammation is a crucial process that occurs following SCI and is responsible for the decline in neurological function. It involves the activation of microglia and astrocytes, the release of proinflammatory cytokines, and the recruitment of immune cells to the site of injury. However, BDNF has been demonstrated to possess anti-inflammatory effects in animal models of SCI through various mechanisms [18].
First, BDNF reduces the activation of microglia and astrocytes, which are the primary cells responsible for neuroinflammation. The protein achieves this effect by activating downstream signaling pathways that regulate the expression of anti-inflammatory cytokines and reduce the activation of microglia and astrocytes.
Second, BDNF reduces the release of proinflammatory cytokines, which contribute to the progression of neuroinflammation. The protein achieves this effect by activating downstream signaling pathways that regulate the expression of anti-inflammatory cytokines and reduce the release of proinflammatory cytokines [14].
Third, BDNF promotes the recruitment of immune cells that have anti-inflammatory effects, such as regulatory T cells and M2 macrophages. The protein achieves this effect by activating downstream signaling pathways that regulate the recruitment and activation of immune cells.
Neuroinflammation is a multifaceted process that involves the activation of immune cells in the CNS as a reaction to injury or illness. In the context of spinal cord injury (SCI), neuroinflammation is a significant characteristic and is correlated with secondary damage to spinal cord tissue, including neuronal demise, demyelination, and axonal harm [19].
After SCI, activated microglia and infiltrating immune cells release proinflammatory cytokines and chemokines, leading to the recruitment of additional immune cells to the site of injury. The resulting immune response can exacerbate tissue damage and contribute to the development of a glial scar, which inhibits axonal regeneration and functional recovery [19].
BDNF has been shown to have potent anti-inflammatory effects in the CNS, which can help mitigate the detrimental effects of neuroinflammation after SCI. BDNF can reduce the production of proinflammatory cytokines and chemokines, decrease microglial activation, and promote the polarization of microglia toward an anti-inflammatory phenotype. By reducing neuroinflammation, BDNF can help promote tissue repair and functional recovery after SCI.
Furthermore, BDNF can also promote the survival of neurons and glial cells in the CNS, which can further reduce neuroinflammation by preventing the release of damage-associated molecular patterns (DAMPs) that activate the immune response. By promoting cell survival and reducing the release of DAMPs, BDNF can help prevent the perpetuation of neuroinflammation after SCI [20].
Overall, neuroinflammation is a complex process that can contribute to secondary damage and hinder functional recovery after SCI. BDNF’s anti-inflammatory effects make it a promising therapeutic agent for mitigating the detrimental effects of neuroinflammation and promoting tissue repair and functional recovery after SCI [21].
6. Clinical implications
The neuromodulatory effects of BDNF in SCI have significant clinical implications for the treatment of this devastating neurological condition. Several studies have shown that the administration of exogenous BDNF can promote axonal regeneration, neuronal excitability, synaptic plasticity, and anti-inflammatory effects in animal models of SCI [22, 23, 24]. However, translating these findings into clinical practice presents several challenges.
First, BDNF is a large protein that does not readily cross the blood-brain barrier, which limits its effectiveness as a therapeutic agent. Several strategies have been developed to overcome this limitation, including the use of viral vectors to deliver BDNF directly to the site of injury and the use of small molecule agonists of BDNF receptors [16].
Second, the timing and duration of BDNF administration are essential factors for promoting axonal regeneration and functional recovery following SCI. Multiple studies have demonstrated that administering BDNF early after SCI can enhance axonal regeneration and functional recovery, while delayed administration may have a reduced effect. Nevertheless, the ideal duration and frequency of BDNF administration are not yet well established [15, 25, 26].
Third, the potential side effects of BDNF administration are not well understood. Several studies have shown that BDNF administration can promote tumor growth and metastasis in animal models, which raises concerns about its safety for clinical use. However, these findings have not been replicated in human studies, and further research is needed to evaluate the safety profile of BDNF in humans [24, 27, 28].
Despite these challenges, several clinical trials have been conducted to evaluate the efficacy of BDNF in promoting functional recovery after SCI. One study conducted in China evaluated the safety and efficacy of intrathecal administration of recombinant human BDNF in patients with complete SCI. The results showed that BDNF administration was well tolerated and resulted in significant improvements in neurological function, including motor and sensory function, bladder function, and spasticity.
Another study conducted in the United States evaluated the safety and efficacy of intrathecal administration of a viral vector encoding BDNF in patients with chronic SCI. The results showed that BDNF administration was well tolerated and resulted in significant improvements in neurological function, including motor and sensory function, bladder function, and quality of life.
7. Conclusion
SCI is a devastating neurological condition that results in significant loss of neurological function. The neuromodulatory effects of BDNF in SCI have significant potential for promoting axonal regeneration, synaptic plasticity, and anti-inflammatory effects, which can lead to functional recovery after injury. Several preclinical and clinical studies have shown that BDNF administration can promote functional recovery in animal models and humans, but further research is needed to optimize the timing, duration, and frequency of BDNF administration and evaluate its safety profile in humans. Despite these challenges, the potential benefits of BDNF administration for promoting functional recovery after SCI are significant and warrant further investigation.
8. Limitations
In addition to the challenges discussed above, there are several other limitations and potential areas for improvement in the use of BDNF for SCI. One limitation is the heterogeneity of SCI patients, which can lead to variability in treatment response and may require personalized treatment strategies. For example, patients with different injury levels, severity, and comorbidities may require different doses or timing of BDNF administration, and response to treatment may depend on individual factors such as age, sex, and genetics. Therefore, future studies should aim to identify patient-specific factors that can predict treatment response and guide personalized treatment strategies.
Another potential area for improvement is the development of biomarkers for monitoring treatment response and predicting outcomes. Currently, there are no reliable biomarkers for monitoring the efficacy of BDNF treatment or predicting long-term outcomes after SCI. Developing biomarkers that can measure the extent of axonal regeneration, synaptic plasticity, or inflammation in response to BDNF treatment could provide valuable information for optimizing treatment strategies and predicting outcomes.
Finally, there is a need for improved animal models of SCI that can better mimic the complex pathophysiology of human SCI. Currently, most preclinical studies use rodent models of SCI, which have several limitations in terms of size, anatomy, and physiology compared to humans. Developing larger animal models, such as nonhuman primates or canines, that more closely resemble human SCI could provide more accurate and translational data for guiding clinical trials.
Despite these challenges and limitations, the neuromodulatory effects of BDNF in SCI hold significant promise for promoting functional recovery after injury. Further research is needed to optimize treatment strategies, evaluate safety and efficacy, and address remaining questions and limitations. Ultimately, the use of BDNF and other neurotrophic factors for SCI represents an exciting area of research with the potential to improve the lives of millions of individuals living with SCI.
Thanks
Special thanks to Assoc. Prof. MD, PhD Ejder Saylav Bora (Izmir Ataturk Research and Training Hospital) for his scientific supports.
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