<p>A Study of Antidepressant Effect and Mechanism on Intranasal Delivery of BDNF-HA2TAT/AAV to Rats with Post-Stroke Depression</p>

Abstract

Post-stroke depression (PSD) is one of the most frequent neuropsychiatric disorders associated with stroke characterized by depression. The neuroplasticity hypothesis postulates that loss of brain-derived neurotrophic factor (BDNF) plays a major role in pathophysiology of PSD, and restoration of it may represent a critical mechanism underlying antidepressant efficacy. Methods: In previous studies, we designed a new fusion gene, HA2TAT-BDNF, and cloned it into adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for the delivery of BDNF to central nervous system (CNS) via nose-brain pathway. In this study, we used it to explore the antidepressant effects on PSD rats through behavioral and various histological methods, and try to find out its specific mechanism. Results: Compared with the control group, the PSD+AAV group showed decreased sucrose consumption percentage in the sucrose preference test (SPT) (P < 0.001) and prolonged immobility in the forced swimming test (FST) (P=0.000). However, the nasal administration of BDNF-HA2TAT/AAV reversed results of these two behavioral tests (P>0.05, P >0.05), showing an adequate antidepressant effect. Compared with the control group, the concentrations of BDNF mRNA and protein in the hippocampus (P< 0.05, P < 0.01) and prefrontal cortex (P < 0.01, P < 0.01) of PSD rats both decreased. Increased BDNF mRNA and protein expression was observed in the prefrontal cortex (P > 0.05, P < 0.05), without notable change in the hippocampus (P < 0.05, P < 0.001) of PSD+BDNF rats. Conclusion: These results suggest that BDNF reductions in the prefrontal cortex and hippocampus are associated with the development of post-stroke depression, and that increased levels of BDNF in the prefrontal cortex could be used as a therapeutic target to treat PSD. However, the exact mechanism of BDNF action remains unclear in this regard, hindering the wider application of our method. We expect that our research could facilitate the exploration of pathogenesis and the new treatment method of PSD.

Applications of Acupuncture Therapy in Modulating the Plasticity of Neurodegenerative Disease and Depression: Do MicroRNA and Neurotrophin BDNF Shed Light on the Underlying Mechanism?

“…Although the structural and functional changes implicated in the relationship between depression and neurodegeneration seem to be highly complex, excitingly, several studies have shown altered BDNF production and secretion in a variety of neurodegenerative diseases as well as in depression [ 136 ]. Overall, BDNF is one of the key molecules modulating and linking brain plasticity, and the neuroplasticity hypothesis postulates that the loss of BDNF plays a major role in the pathophysiology of poststroke depression and depression with AD [ 137 , 138 ]. Similarly, in a short review, while providing evidence of shared biological substrates between PD and depression, neuroplasticity was underscored by the roles of BDNF [ 139 ].…”

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

“…Intranasal delivery of an AAV2 construct expressing BDNF fused with cell-penetrating peptides TAT and HA2 to a rat model of poststroke depression reversed the basal decreased sucrose consumption and prolonged immobility in the forced swimming test ( C. Chen et al, 2020 ).…”

Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation

“…The authors declare no conflict of interest. Alter inflammatory pathways Improved memory [39,42] ↓ astrocyte/microglia activation [40,41] Improves neuroinflammation Improved memory [46] Traumatic brain injury ↓ lesion volume; ↓ microglia activation [47] FGF Alzheimer's disease ↑ neurogenesis; ↓ hippocampal loss Improved memory [49,50] ↓ Aβ deposition, tau hyperphosphorylation, astrocyte/microglia activation Improved memory [59] Neuroinflammation modifies microglia signaling, DAMPs, PAMPs [51] Parkinson's disease ↑ dopaminergic neuron function; ↓ astrocyte/microglia activation Improves behavioral deficit [53] Stroke (hypoxia/ischemia) ↓ pro-inflammatory cytokines [59] BDNF Depression Improved behavior [63] Parkinson's disease ↑ dopaminergic neurons Improved motor function [68] Stroke No change in infarct volume; altered neuroinflammatory profile [79] NGF Human GBS meningitis* Improved neurological impairment [83] Human traumatic brain injury* ↑ neurogenesis Improved neurological impairment [86] Traumatic brain injury ↓ edema and cell death [82] PACAP Alzheimer's disease ↓ RAGE Improved memory [26,88] Huntington's disease ↑ BDNF, synapses;↓ mutant huntingtin aggregates Improved memory [90] Muscular dystrophy (SBMA) ↑ polyQ-AR degradation; improve neurotoxicity [89] MSC-oligodendrocytes Multiple sclerosis (EAE) ↓ neuroinflammation; ↑ myelination Improved behavior [186] IGF-1, insulin-like growth factor-1; FGF, fibroblast growth factor; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; PACAP, pituitary adenylate-cyclase-activating polypeptide 38; GBS, group B Streptococcus; SBMA, spinobulbar muscular atrophy; EAE, experimental autoimmune encephalomyelitis; NBP, DL-3-n-butylphthalide; TGF, transforming growth factor; G-CSF, granulocyte-colony stimulating factor; IL, interleukin; TNF, tumor necrosis factor; MSC, mesenchymal stem cell; EV, extracellular vesicle; PMN, polymorphonuclear neutrophils; DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; RAGE, receptor for advanced glycation end products; polyQ-AR, polyglutamine androgen receptor; BBB, blood-brain barrier; Aβ, amyloid beta; P-gp, p-glycoprotein; VEGF, vascular endothelial growth factor; eNOS, endothelial nitric oxide synthase; Ido-1, indoleamine 2,3-dioxygenase; mTORC1, mammalian target of rapamycin complex 1.The effects following intranasal...…”

“…Transgenic animal models of AD have shown an inverse correlation between BDNF levels and cognitive performance [ 62 ]. Decreased BDNF levels in brain have been associated with clinical depression [ 63 , 64 ], PD [ 65 ], and AD [ 66 ].…”

“…The use of IN delivery of BDNF has been shown to be a promising alternative. It can reduce depression-like phenotype in rats [ 63 ]. In 2014, Chen and colleagues advanced the CNS delivery of BDNF, while reducing peripheral confounds, by combining IN delivery of BDNF with focused ultrasound (FUS).…”