Brain-derived Neurotrophic Factor Function Research Articles

BDNF Modulation by microRNAs: An Update on the Experimental Evidence.

MicroRNAs can interfere with protein function by suppressing their messenger RNA translation or the synthesis of its related factors. The function of brain-derived neurotrophic factor (BDNF) is essential to the proper formation and function of the nervous system and is seen to be regulated by many microRNAs. However, understanding how microRNAs influence BDNF actions within cells requires a wider comprehension of their integrative regulatory mechanisms. Aim: In this literature review, we have synthesized the evidence of microRNA regulation on BDNF in cells and tissues, and provided an analytical discussion about direct and indirect mechanisms that appeared to be involved in BDNF regulation by microRNAs. Methods: Searches were conducted on PubMed.gov using the terms "BDNF" AND "MicroRNA" and "brain-derived neurotrophic factor" AND "MicroRNA", updated on 1 September 2023. Papers without open access were requested from the authors. One hundred and seventy-one papers were included for review and discussion. Results and Discussion: The local regulation of BDNF by microRNAs involves a complex interaction between a series of microRNAs with target proteins that can either inhibit or enhance BDNF expression, at the core of cell metabolism. Therefore, understanding this homeostatic balance provides resources for the future development of vector-delivery-based therapies for the neuroprotective effects of BDNF.

The effect of olanzapine on spatial memory impairment, depressive-like behavior, pain perception, and BDNF and synaptophysin expression following childhood chronic unpredictable mild stress in adult male and female rats

Chronic unpredictable mild stress (CUMS) method has been introduced as a rodent model of depression. On the other hand, olanzapine, as an antipsychotic, can induce antidepressant and antipsychotic effects. Also, olanzapine may improve cognitive functions. Both CUMS and olanzapine can also affect the expression level of brain-derived neurotrophic factor (BDNF) and synaptophysin, the molecular factors involved in synaptic function, and learning and memory. In this study, we investigated the effect of olanzapine on locomotor activity (using open field test), pain threshold (using hot plate), depressive-like behavior (using forced swim test), spatial learning and memory (using Morris water maze), and BDNF and synaptophysin hippocampal expression (using real-time PCR) in both male and female CUMS rats. CUMS was performed for three consecutive weeks. Olanzapine was also injected intraperitoneally at the dose of 5 mg/kg. Our data showed that olanzapine can reverse the effects of CUMS on behavioral functions and BDNF and synaptophysin expression levels in the hippocampus of both males and females. It was also shown that olanzapine effects on spatial memory, pain perception, and BDNF and synaptophysin level were stronger in females than males. In conclusion, we suggested that the therapeutic effects of olanzapine in CUMS rats may be closely related to the function of BDNF and synaptophysin. Also, the therapeutic effects of olanzapine may be stronger in females. Therefore, and for the first time, we showed that there may be a sex difference in the effects of olanzapine on behavioral and molecular changes following CUMS.

Brain-derived neurotrophic factor scales presynaptic calcium transients to modulate excitatory neurotransmission

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic physiology, as well as mechanisms underlying various neuropsychiatric diseases and their treatment. Despite its clear physiological role and disease relevance, BDNF's function at the presynaptic terminal, a fundamental unit of neurotransmission, remains poorly understood. In this study, we evaluated single synapse dynamics using optical imaging techniques in hippocampal cell cultures. We find that exogenous BDNF selectively increases evoked excitatory neurotransmission without affecting spontaneous neurotransmission. However, acutely blocking endogenous BDNF has no effect on evoked or spontaneous release, demonstrating that different approaches to studying BDNF may yield different results. When we suppressed BDNF-Tropomyosin receptor kinase B (TrkB) activity chronically over a period of days to weeks using a mouse line enabling conditional knockout of TrkB, we found that evoked glutamate release was significantly decreased while spontaneous release remained unchanged. Moreover, chronic blockade of BDNF-TrkB activity selectively downscales evoked calcium transients without affecting spontaneous calcium events. Via pharmacological blockade by voltage-gated calcium channel (VGCC) selective blockers, we found that the changes in evoked calcium transients are mediated by the P/Q subtype of VGCCs. These results suggest that BDNF-TrkB activity increases presynaptic VGCC activity to selectively increase evoked glutamate release.

Emerging Insights into the Role of BDNF on Health and Disease in Periphery.

Brain-derived neurotrophic factor (BDNF) is a growth factor that promotes the survival and growth of developing neurons. It also enhances circuit formation to synaptic transmission for mature neurons in the brain. However, reduced BDNF expression and single nucleotide polymorphisms (SNP) are reported to be associated with functional deficit and disease development in the brain, suggesting that BDNF is a crucial molecule for brain health. Interestingly, BDNF is also expressed in the hypothalamus in appetite and energy metabolism. Previous reports demonstrated that BDNF knockout mice exhibited overeating and obesity phenotypes remarkably. Therefore, we could raise a hypothesis that the loss of function of BDNF may be associated with metabolic syndrome and peripheral diseases. In this review, we describe our recent finding that BDNF knockout mice develop metabolic dysfunction-associated steatohepatitis and recent reports demonstrating the role of one of the BDNF receptors, TrkB-T1, in some peripheral organ functions and diseases, and would provide an insight into the role of BDNF beyond the brain.

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aβ axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

Brain neurotrophic factor BDNF: new data, functions and questions

The brain-derived neurotrophic factor (BDNF) is a key modulator of neurogenesis, synaptogenesis, neuroregeneration, and cell differentiation in the nervous system. Impaired BDNF functioning is a characteristic of various neurological diseases, such as Alzheimer’s disease, multiple sclerosis, and depressive disorders. There is recent evidence that patients with COVID-19 have reduced BDNF levels in the blood plasma. Furthermore, exogenous BDNF and its mimetics have demonstrated therapeutic potential.
 In this review, we systematized data of the BDNF gene structure, epigenetic and microRNA-mediated regulation of its expression, transcriptional variants of BDNF, and the effects of BDNF on neuronal and oligodendroglial differentiation. Further, we point out the gaps in the current knowledge about BDNF and propose experiments that can expand such knowledge and the range of possibilities for using BDNF in biomedicine. These include determining the expression pattern of all BDNF gene transcripts at different stages of differentiation and in different cell subpopulations and studying the role of receptor-independent BDNF signaling, circadian fluctuations in BDNF levels, and their role in physiological and pathophysiological conditions. Finally, for translational medicine, evaluating the effect of BDNF mimetics (including those immobilized on three-dimensional scaffolds for tissue engineering) on neuronal and oligodendroglial differentiation of pluripotent and polypotent cells and identifying molecular regulators of BDNF transcription, including small molecules and microRNAs capable of regulating BDNF gene expression, are crucial.

How BDNF affects working memory in acute sleep deprivation: The mediating role of spontaneous brain activity

The brain-derived neurotrophic factor (BDNF) mediates the plasticity associated with memory processing, and compensatorily increases after acute sleep deprivation (SD). However, whether the altered spontaneous brain activity mediates the association between BDNF and working memory in SD remains unknown. Here, we aimed to probe the mediating role of the spontaneous brain activity between plasma BDNF and WM function in SD. A total of 30 healthy subjects with regular sleep were enrolled in this study. Resting-sate functional magnetic resonance imaging (fMRI) scans and the peripheral blood were collected before and after 24 h SD. All participants also received n-back task assessing working memory (WM) performance. The amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) were calculated to reflect the intensity of regional spontaneous brain activity. Plasma BDNF was measured by sandwich ELISA. Our results revealed a significant decline in WM and increase in plasma BDNF level after SD, and negative association between the changed WM performance and plasma BDNF level. Specially, the ALFF of the left inferior parietal cortex and right inferior frontal cortex, and fALFF of the left anterior cingulate and medial prefrontal cortex and left posterior opercular cortex regulated the association between the BDNF and one-back reaction time respectively. Our results suggest that the association between BDNF and working memory may be mediated through regional spontaneous brain activity involving in the cerebral cortex, which may provide new sight into the interaction between neurotrophic factors and cognition, and potential targets for noninvasive brain stimulation on WM decline after acute SD.

BDNF and Lactate as Modulators of Hippocampal CA3 Network Physiology.

Growing evidence supports the notion that brain-derived neurotrophic factor (BDNF) and lactate are potent modulators of mammalian brain function. The modulatory actions of those biomolecules influence a wide range of neuronal responses, from the shaping of neuronal excitability to the induction and expression of structural and synaptic plasticity. The biological actions of BDNF and lactate are mediated by their cognate receptors and specific transporters located in the neuronal membrane. Canonical functions of BDNF occur via the tropomyosin-related kinase B receptor (TrkB), whereas lactate acts via monocarboxylate transporters or the hydroxycarboxylic acid receptor 1 (HCAR1). Both receptors are highly expressed in the central nervous system, and some of their physiological actions are particularly well characterized in the hippocampus, a brain structure involved in the neurophysiology of learning and memory. The multifarious neuronal circuitry between the axons of the dentate gyrus granule cells, mossy fibers (MF), and pyramidal neurons of area CA3 is of great interest given its role in specific mnemonic processes and involvement in a growing number of brain disorders. Whereas the modulation exerted by BDNF via TrkB has been extensively studied, the influence of lactate via HCAR1 on the properties of the MF-CA3 circuit is an emerging field. In this review, we discuss the role of both systems in the modulation of brain physiology, with emphasis on the hippocampal CA3 network. We complement this review with original data that suggest cross-modulation is exerted by these two independent neuromodulatory systems.

The altered hippocampal functional connectivity and serum brain-derived neurotrophic factor level predict cognitive decline in patients with knee osteoarthritis.

Patients with knee osteoarthritis (KOA) often suffer from cognitive decline and increased dementia risk, but the neurobiological mechanisms remain unclear. In this study, we evaluated cognitive performance and collected brain magnetic resonance imaging (MRI) data and blood samples from cognitively normal KOA patients at baseline sessions and reevaluated their cognition after 5years. We also collected MRI data from matched healthy controls. Results showed that KOA patients exhibited dysregulated functional connectivities between the hippocampus and thalamus/superior frontal gyrus compared with healthy controls. The altered hippocampal functional connectivities were associated with serum brain-derived neurotrophic factor (BDNF) levels and spatial expression of genes enriched in synaptic plasticity. The hippocampus-thalamus functional connectivity was significantly correlated with patients' memory scores. Moreover, the baseline hippocampus-thalamus functional connectivity and BDNF levels significantly predicted the development of cognitive decline in KOA patients in the follow-up session. Our findings provide insight into the neurobiological underpinnings of KOA and cognitive decline.

An 840 kb distant upstream enhancer is a crucial regulator of catecholamine-dependent expression of the Bdnf gene in astrocytes.

Brain-derived neurotrophic factor (BDNF) plays a fundamental role in the developing and adult nervous system, contributing to neuronal survival, differentiation, and synaptic plasticity. Dysregulation of BDNF synthesis, secretion or signaling has been associated with many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Although the transcriptional regulation of the Bdnf gene has been extensively studied in neurons, less is known about the regulation and function of BDNF in non-neuronal cells. The most abundant type of non-neuronal cells in the brain, astrocytes, express BDNF in response to catecholamines. However, genetic elements responsible for this regulation have not been identified. Here,we investigated four potential Bdnf enhancer regions and based on reporter gene assays, CRISPR/Cas9 engineering and CAPTURE-3C-sequencing we conclude that a region 840 kb upstream of the Bdnf gene regulates catecholamine-dependent expression of Bdnf in rodent astrocytes. We also provide evidence that this regulation is mediated by CREB and AP1 family transcription factors. This is the first report of an enhancer coordinating the transcription of Bdnf gene in non-neuronal cells.

The effects of curcumin on Brain-Derived Neurotrophic Factor expression in neurodegenerative disorders.

Brain-Derived Neurotrophic Factor (BDNF) is a crucial molecule implicated in plastic modifications related to learning and memory. The expression of BDNF is highly regulated, which can lead to significant variability in BDNF levels in healthy subjects. Changes in BDNF expression might be associated with neuropsychiatric diseases, particularly in structures important for memory processes, including the hippocampus and parahippocampal areas. Curcumin is a natural polyphenolic compound that has great potential for the prevention and treatment of age-related disorders by regulating and activating the expression of neural protective proteins such as BDNF. This review discusses and analyzes the available scientific literature on the effects of curcumin on BDNF production and function in both in vitro and in vivo models of disease.

The Role of BDNF as a Biomarker in Cognitive and Sensory Neurodegeneration.

Brain-derived neurotrophic factor (BDNF) has a crucial function in the central nervous system and in sensory structures including olfactory and auditory systems. Many studies have highlighted the protective effects of BDNF in the brain, showing how it can promote neuronal growth and survival and modulate synaptic plasticity. On the other hand, conflicting data about BDNF expression and functions in the cochlear and in olfactory structures have been reported. Several clinical and experimental research studies showed alterations in BDNF levels in neurodegenerative diseases affecting the central and peripheral nervous system, suggesting that BDNF can be a promising biomarker in most neurodegenerative conditions, including Alzheimer's disease, shearing loss, or olfactory impairment. Here, we summarize current research concerning BDNF functions in brain and in sensory domains (olfaction and hearing), focusing on the effects of the BDNF/TrkB signalling pathway activation in both physiological and pathological conditions. Finally, we review significant studies highlighting the possibility to target BDNF as a biomarker in early diagnosis of sensory and cognitive neurodegeneration, opening new opportunities to develop effective therapeutic strategies aimed to counteract neurodegeneration.

Expression Pattern and Value of Brain-Derived Neurotrophic Factor in Periodontitis

BackgroundPeriodontitis is a common human disease with an increasing incidence. Brain-derived neurotrophic factor (BDNF) is known to play a crucial role in the regeneration of periodontal tissue; however, the expression, methylation level, molecular function, and clinical value of BDNF in periodontitis require further investigation. This study aimed to investigate the expression and potential functions of BDNF in periodontitis. MethodsRNA expression and methylation data were obtained from the Gene Expression Omnibus (GEO) database, and the expression and methylation levels of BDNF were compared between periodontitis and normal tissues. In addition, bioinformatics analysis was performed to investigate the downstream molecular functions of BDNF. Finally, Reverse transcription Quantitative real-time polymerase chain reaction was performed to determine the level of BDNF expression in periodontitis and normal tissues. ResultsGEO database analysis revealed that BDNF was hypermethylated in periodontitis tissues and that its expression was downregulated. Reverse transcription Quantitative real-time polymerase chain reaction confirmed that BDNF expression was downregulated in periodontitis tissues. Several genes that interact with BDNF were determined using a protein–protein interaction network. Functional analysis of BDNF revealed that it was enriched in the Gene Ontology terms cytoplasmic dynein complex, glutathione transferase activity, and glycoside metabolic process. Kyoto Encyclopedia of Genes and Genomes analysis suggested that BDNF was associated with the mechanistic target of rapamycin signaling pathway, fatty acid metabolism, the Janus kinase-signal transducer and activator of transcription signaling pathway, glutathione metabolism, and others. Furthermore, the level of BDNF expression was correlated with the immune infiltration degree of B cells and CD4+ T cells. ConclusionsThis study shown that BDNF was hypermethylated and downregulated in periodontitis tissues, which could be a biomarker and treatment target of periodontitis.

Effects of brain-derived neurotrophic factor and adeno-associated viral vector on morphine-induced condition through target concentration changes in the ventral tegmental area and nucleus accumbens

Morphine remains the standard analgesic for severe pain. However, the clinical use of morphine is limited by the innate tendency of opiates to become addictive. Brain-derived neurotrophic factor (BDNF) is a growth factor that is protective against many mental disorders. This study aimed to evaluate the protective function of BDNF on morphine addiction based on the behavioural sensitisation (BS) model and assess potential changes in downstream molecular tropomyosin-related kinase receptor B (TrkB) and cyclic adenosine monophosphate response element binding protein (CREB) expression caused by overexpression of BDNF. We divided 64 male C57BL/6 J mice into saline, morphine, morphine plus adeno-associated viral vector (AAV), and morphine plus BDNF groups. After administering the treatments, behavioural tests were conducted during the development and expression phases of BS, followed by a western blot analysis. All data were analysed by one- or two-way analysis of variance. The overexpression of BDNF in the ventral tegmental area (VTA) caused by BDNF-AAV injection decreased the total distance of locomotion in mice who underwent morphine-induced BS and increased the concentrations of BDNF, TrkB, and CREB in the VTA and nucleus accumbens (NAc). BDNF exerts protective effects against morphine-induced BS by altering target gene expression in the VTA and NAc.

Oral Administration of TrkB Agonist, 7, 8-Dihydroxyflavone Regenerates Hair Cells and Restores Function after Gentamicin-Induced Vestibular Injury in Guinea Pig.

The causes of vestibular dysfunction include the loss of hair cells (HCs), synapses beneath the HCs, and nerve fibers. 7, 8-dihydroxyflavone (DHF) mimics the physiological functions of brain-derived neurotrophic factor. We investigated the effects of the orally-administered DHF in the guinea pig crista ampullaris after gentamicin (GM)-induced injury. Twenty animals treated with GM received daily administration of DHF or saline for 14 or 28 days (DHF (+) or DHF (-) group; N = 5, each). At 14 days after GM treatment, almost all of the HCs had disappeared in both groups. At 28 days, the HCs number in DHF (+) and DHF (-) groups was 74% and 49%, respectively, compared to GM-untreated control. In the ampullary nerves, neurofilament 200 positive rate in the DHF (+) group was 91% at 28 days, which was significantly higher than 42% in DHF (-). On day 28, the synaptic connections observed between C-terminal-binding protein 2-positive and postsynaptic density protein-95-positive puncta were restored, and caloric response was significantly improved in DHF (+) group (canal paresis: 57.4% in DHF (+) and 100% in DHF (-)). Taken together, the oral administration of DHF may be a novel therapeutic approach for treating vestibular dysfunction in humans.

Melatonin Treatment of Circadian Rhythm Sleep-Wake Disorder in Obese Children Affects the Brain-Derived Neurotrophic Factor Level.

Previous studies proved that the brain-derived neurotrophic factor (BDNF) is correlated with sleep regulation, yet how BDNF functions and reacts in the melatonin treatment of circadian rhythm sleep-wake disorder (CRSWD) among obese children remain enigmatic. Focusing on CRSWD in obese children, this study monitored their sleep efficiency and serum BDNF level changes during the treatment of melatonin. In total, 35 obese children diagnosed with CRSWD were included in this study and administrated melatonin (3 mg/night) for 3 months. Blood samples were collected 24 hours before and after the treatment (08:00, 12:00, 16:00, 20:00, 24:00, and 04:00). Subsequently, the plasma melatonin level and serum BDNF level were measured by enzyme-linked immunosorbent assay. Sleep parameters, including sleep quality, Pittsburgh Sleep Quality Index as well as melatonin and BDNF levels before and after treatment, were recorded to profile the effectiveness and safety of melatonin treatment. Melatonin treatment increased plasma melatonin concentration and restored circadian rhythm. Besides, the serum BDNF level showed a significant increase, representing a strong positive correlation with melatonin concentration (p = 0.026). Patients experienced much-improved sleep efficiency (P < 0.001), with longer actual sleep time (P < 0.001), shorter sleep onset latency, and fewer awakenings after treatment (P < 0.001). Besides, melatonin was well tolerated by patients without producing severe side effects. Melatonin treatment effectively improved CRSWD among obese children with their serum BDNF levels increased, indicating that BDNF is a key regulator in CRSWD in obese children. This study may offer theoretical support for melatonin treatment of CRSWD in obese children.

Brain-derived neurotrophic factor G196A (rs6265) gene polymorphism increases Turner syndrome susceptibility

ABSTRACT Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family. It plays a significant role in the regulation of brain metabolic activity, modification of synaptic efficacy, and enhances neuronal survival. A common naturally occurring allelic variation, i.e. G196A (Val66 Met, rs6265) of the BDNF gene is implicated in neuroplasticity. This study analyzes its expression levels and determines the frequency of BDNF G196A gene polymorphism in women with Turner syndrome (TS) compared to the controls. This case–control study comprised 14 TS patients and 8 healthy individuals. The expression levels of BDNF gene in TS patients were checked by qPCR. For BDNF gene, a dynamic expression range along with the presence of G196A polymorphism was found across all TS patients. The effects of Val66 Met mutation on BDNF protein structure and function were studied by molecular dynamics simulations of wild and mutant (Val66 Met) forms. The analysis of different trajectories generated by simulation showed that there was a significant change in the protein structure due to Val66 Met polymorphism, which might lead to functional impairment. This is first time we are reporting the association of BDNF G196A gene polymorphism with TS risk. Our study suggests that in turner patients, BDNF G196A polymorphism may be an important genetic factor predisposing to neuroplasticity risk and can be exploited as diagnostic/prognostic marker for TS. Further study on a large number of TS samples will prove this point beyond doubts or otherwise enriching the much desired repertoire of personalized medicine.

The Function of BDNF and Its Receptor in the Male Genitourinary System and Its Potential Clinical Application

Background: Brain-derived neurotrophic factor (BDNF), as a member of the nerve growth factor family, has been mentioned more and more frequently in recent literature reports. Among them, content about the male genitourinary system is also increasing. Objective and Rationale: BDNF plays an important role in the male genitourinary system. At the same time, the literature in this field is constantly increasing. Therefore, we systematically summarized the literature in order to more intuitively show the function of BDNF and its receptor in the male genitourinary system and its potential clinical application. Search Methods: An electronic search of, e.g., PubMed, scholar.google and Scopus, for articles relating to BDNF and its receptor in the male genitourinary system. Outcomes: In the male genitourinary system, BDNF and its receptors TrkB and p75 participate in a series of normal physiological activities, such as the maturation and morphogenesis of testes and epididymis and maintenance of isolated sperm motility. Similarly, an imbalance of the circulating concentration of BDNF also mediates the pathophysiological process of many diseases, such as prostate cancer, benign prostatic hyperplasia, male infertility, diabetes erectile dysfunction, penile sclerosis, and bladder fibrosis. As a consequence, we conclude that BDNF and its receptor are key regulatory proteins in the male genitourinary system, which can be used as potential therapeutic targets and markers for disease diagnosis.

Analysis of microglial BDNF function and expression in the motor cortex.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates several aspects of brain function. Although numerous studies have demonstrated the expression and function of BDNF in neurons, its expression in microglia remains controversial. Using a combination of genetic tools and fluorescence imaging, we analyzed BDNF expression patterns and investigated the effect of microglial Bdnf deletion on neuronal activity, early-stage spine formation, and microglia-neuron attraction in the motor cortex. We did not detect BDNF expression in microglia at the transcriptional or translational level, in physiological or pathological conditions, and none of the assessed neuronal functions were found to be affected in conditional Bdnf knockout mice. Our results suggest that microglia do not express BDNF in sufficient amounts to modulate neuronal function.

The development of novel multifunctional drug system 7,8-DHF@ZIF-8 and its potential application in bone defect healing

Physical exercise has long been considered an essential regulator of bone formation. Recent studies have shown that brain-derived neurotrophic factor (BDNF) is an important cytokine released during physical exercise to promote osteogenic differentiation and facilitate the bone defect healing process. In this study, we developed a multifunctional system 7,8-DHF@ZIF-8, which combines the superior osteogenesis and angiogenesis properties of ZIF-8 and the unique capability of 7,8-DHF to mimic the function of BDNF to compensate for the routine physical exercise missed during the bone defect period. Various material characterizations were performed to confirm the successful synthesis of 7,8-DHF@ZIF-8. Drug release experiments suggested that 7,8-DHF@ZIF-8 could achieve slow diffusive release under physiological conditions within seven days. In vitro cell experiments indicated that low concentrations of ZIF-8 and 7,8-DHF@ZIF-8 could significantly promote the proliferation of MC3T3-E1 cells. Moreover, as proved by RT-QPCR analysis, incorporating 7,8-DHF into ZIF-8 could further enhance osteogenesis and angiogenesis-related gene expression. Therefore, we believe that the multifunctional drug system 7,8-DHF@ZIF-8 should have promising applications to facilitate bone defect healing.