Search Results (363)

Background/Objectives: Management of bipolar disorder is marked by variability in lithium response, with responders constituting a distinct clinical subgroup. Although pharmacogenetic studies implicate polymorphisms in neuroplasticity-related genes (BDNF) and hypothalamic–pituitary–adrenal (HPA) axis regulators (NR3C1), the underlying biophysical mechanisms remain poorly characterized. This study aims to bridge this structural–mechanistic gap by quantifying the atomic-level effects of key lithium-response polymorphisms on protein–protein interaction stability and conformational dynamics. Methods: Variant sequences for BDNF rs6265 and NR3C1 rs56149945 were generated and structurally modeled with SWISS-MODEL. Protein–protein interaction analyses focused on the BDNF–TrkB and NR3C1–FKBP5 systems. Structural alignment and conformational comparisons were performed with ChimeraX and US-align, while interaction energetics were evaluated with PRODIGY and HawkDock. Conformational flexibility was assessed using CABS-flex through RMSF analysis. Results: Structural validation showed acceptable model quality. Binding analyses indicated stronger interactions in the variant complexes. In the BDNF–TrkB complex, binding affinity shifted from −13.8 to −15.1 kcal/mol with an ~8.5-fold lower dissociation constant, while the NR3C1–FKBP5 variant complex shifted from −16.3 to −18.8 kcal/mol with an ~65-fold lower dissociation constant. MM/GBSA calculations supported increased stability, with binding energies changing from −61.98 to −83.91 kcal/mol (BDNF–TrkB) and from −18.88 to −31.25 kcal/mol (NR3C1–FKBP5). Structural superposition showed high conservation of global folds (pruned RMSD 0.779 Å and 0.310 Å; TM-scores 0.753 and 0.967). RMSF profiles were largely overlapping, indicating localized interface adjustments rather than global conformational changes. Conclusions: These findings suggest that lithium-response polymorphisms may modulate protein–protein interaction stability while preserving overall structure, providing a structural framework for exploring genetic influences on lithium treatment response. Full article

Alzheimer’s disease (AD) is a prevalent chronic neurodegenerative disorder; the progression of this disease is driven by cellular determinants such as oxidative stress and dysregulated neurotrophic signaling. Lavender essential oil is traditionally used in aromatherapy for neuronal regulation and neuroprotection, suggesting its potential neuroprotective effects for chronic neurodegenerative disorders like AD. However, the key active constituents responsible for its benefits and the specific molecular pharmacological mechanisms remain unclear. In this study, we isolated myrtenol from lavender essential oil under the guidance of activity evaluation. Its neuroprotective effects were evaluated in PC12 cells via neurite outgrowth, anti-Aβ/H₂O₂ cytotoxicity, and antioxidant assays. Targets and pathways were explored using inhibitor experiments, cell thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and Western blot. Myrtenol significantly induced neurite outgrowth in PC12 cells and effectively mitigated cytotoxicity and oxidative stress damage induced by Aβ_25–35 and H₂O₂. Mechanistic studies revealed that myrtenol’s effects are associated with the modulation of tyrosine kinase receptor A (TrkA) and insulin-like growth factor-1 receptor (IGF-1R), activating phospholipase C (PLC)/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways to jointly mediate neuroprotection effects against the pathology of AD. This study demonstrates that myrtenol as a highly active component of lavender essential oil possesses NGF-like neuritogenic activity and neuroprotective effects. It provides a foundation for understanding the cellular mechanisms of myrtenol as a small-molecule lead for further investigation in neurodegeneration-related research. Full article

Background/Objectives: Blast-induced hearing loss (BIHL) is a major concern, particularly for military personnel, and is linked to impaired auditory neuron survival and synaptic plasticity. This study investigates the potential of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) to reduce the severity of BIHL and promote recovery in a mouse model. Methods: Eight-week-old male C57BL/6J mice were used. A custom-built, compressed air-driven system utilizing a modified paintball apparatus was employed to deliver controlled unilateral double blasts (~22 psi exposure pressure) to the left ear. The blasts were administered 30 min apart. Immediately following the second blast, mice received either 7,8-DHF (10 mg/kg) or vehicle (10% DMSO) via intraperitoneal injection. Auditory brainstem responses (ABRs) were measured in both ears at baseline (pre-blast) and at several post-exposure time points. Results: The consecutive blast exposure induced a significant elevation in ABR thresholds, indicative of hearing loss, in both the ipsilateral (exposed) and contralateral (unexposed) ears of vehicle-treated mice. Notably, mice treated with 7,8-DHF demonstrated a marked improvement in hearing recovery compared to the vehicle group. Significant reductions in ABR thresholds were observed in the ipsilateral ear at 4 weeks post-blast (p < 0.0001) and in the contralateral ear as early as 1-week post-blast (p = 0.0236). However, the recovery was partial, with ABR thresholds plateauing after 4 weeks. Conclusions: A controlled blast model demonstrates that systemic administration of the TrkB agonist 7,8-DHF exerts a protective effect, partially restoring auditory function after blast injury. This supports the therapeutic potential of targeting the BDNF-TrkB signaling pathway for managing BIHL. Full article

Background/Objectives: Stewartia pseudocamellia Maxim. (S. pseudocamellia) has been reported to possess antioxidant and anti-inflammatory properties and contains various bioactive flavonoids and phenolic compounds. These components may contribute to neuroprotective effects relevant to depression and cognitive dysfunction. This study was conducted to evaluate the effects of 20% ethanolic extract from S. pseudocamellia leaves (ESP) on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive dysfunction in C57BL/6 mice. Methods: C57BL/6 mice were divided into six groups: normal control (NC), normal sample (NS; ESP 100 mg/kg), CUMS, L-theanine (Thea; 4 mg/kg), ESP 50 mg/kg, and ESP 100 mg/kg groups. Phytochemical profiling of ESP was performed using ultra-performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Depressive-like behaviors and cognitive function were assessed, along with stress-related hormonal regulation and associated cellular signaling pathways. Results: Phytochemical profiling of ESP identified procyanidin B2, epicatechin, rutin, catechin gallate, kaempferol 3-O-glucoside, and quercitrin as major constituents. ESP significantly alleviated CUMS-induced depressive-like behaviors and improved spatial learning and memory. These effects were associated with modulation of stress-related hormones in serum and hypothalamic–pituitary–adrenal (HPA) axis–related proteins in the brain. ESP also enhanced antioxidant defense by activating the Nrf2 signaling pathway and improving mitochondrial function. Furthermore, ESP attenuated neuroinflammation and apoptosis by regulating the TLR4/NF-κB and JNK pathways, and promoted neuroplasticity by modulating cholinergic activity, with enhanced BDNF/TrkB signaling in the cerebral cortex and hippocampus. Conclusions: Collectively, these findings suggest that ESP exerts protective effects against CUMS-induced depressive-like behaviors and cognitive deficits in a preclinical model. Full article

Advances in multimodal therapy for high-risk neuroblastomas (NBs) have plateaued, prompting therapeutic initiatives to harness the immune system. NBs, however, are immunologically “cold” and a significant challenge to immunotherapy. Here, in a Jurkat lymphocyte cytotoxicity model, we describe an antigen-independent, cell-mediated mechanism for eliminating NB cells, first detected in PMA-activated low pcDNA-SH-SY5Y and high TrkAIII-SH-SY5Y TrkAIII-expressing cells, which are resistant to Jurkat elimination under normal conditions. Characterization of this mechanism through live cell imaging, adhesion assays, RT-PCR, Western blotting and indirect IF, employing a variety of inhibitors, indicates that it initiates with PMA-induced NB cell CCL2 expression. This results in CCL2 promotion of Jurkat CCR2b expression, CCL2/CCR2b-mediated Jurkat LFA-1 activation and the formation of cytotoxic lipid-raft LFA1/ICAM-1 immune synapses, through which Jurkat m-TRAIL combines with PMA-enhanced NB cell DR5/TRAIL-R2 expression to induce NB cell apoptosis. This mechanism is enhanced by the NB-associated oncoprotein TrkAIII through Shp/Src-regulated c-FLIP sequester and is PD-L1/PD-1-independent and resistant to osteoprotegerin. It eliminates both non-MYCN-amplified (SH-SY5Y and SK-N-SH) and MYCN-amplified (SMS-KCNR) NB cells that exhibit PMA-inducible CCL2 expression but not MYCN-amplified NB cells (IMR-32 and NB-1) that exhibit CCL2 repression, and is offset by reciprocal NB cell-induced Fas-mediated Jurkat cell apoptosis. These findings form a solid foundation for further pre-clinical development aimed at identifying clinically relevant physiological immune cell equivalents and alternative PKC activators, with the ultimate goal of translating this mechanism into an effective immune-therapeutic approach for the treatment of high-risk non-immunogenic NBs, especially NBs that exhibit CCL2 and TrkAIII expression. Full article

Glaucoma is increasingly recognized as an ischemic neurodegenerative disorder that extends beyond elevated intraocular pressure (IOP) to involve complex vascular, metabolic, and inflammatory mechanisms. Retinal ganglion cells are particularly vulnerable to ischemia–reperfusion injury, oxidative stress, and chronic neuroinflammation, leading to progressive disconnection from central visual pathways. Current therapies primarily target IOP reduction but fail to address ischemia-driven neurodegeneration or to restore lost neuronal connectivity. Ischemia triggers excitotoxicity, oxidative stress, and a maladaptive inflammatory response involving activated microglia and astrocytes, perpetuating neuronal injury and suppressing intrinsic regenerative capacity. Thus, restoring neural plasticity and mitigating neuroinflammation represent key unmet therapeutic needs. Psychoplastogens are a class of compounds capable of rapidly enhancing structural and functional neuroplasticity and have recently emerged as promising multitarget agents. Compounds such as ketamine, psilocybin, N,N-dimethyltryptamine (DMT), and some newly synthesized non-hallucinogenic analogs act through convergent signaling pathways involving BDNF–TrkB–mTOR, promoting dendritic growth, synaptogenesis, and glial modulation. Beyond their neurotrophic effects, psychoplastogens seem to exert potent immunomodulatory actions. In this review we will explore the interplay between ischemia, neurodegeneration, neuroinflammation, and impaired plasticity in glaucoma, integrating mechanistic insights from cerebral ischemia. We discuss emerging preclinical evidence supporting psychoplastogens as neurorestorative and anti-inflammatory agents, propose their potential application in ocular ischemic neurodegeneration, and outline translational challenges for future studies. Full article

Hericium erinaceus (H. erinaceus), a medicinal mushroom, is a source of bioactive compounds with demonstrated neuroprotective potential. This activity is primarily attributed to two distinct classes of compounds: erinacines from the mycelium, which potently induce the synthesis of neurotrophins, protein growth factors essential for neuronal survival and health, and hericenones from the fruiting body, which subsequently appear to enhance or potentiate neurotrophin-activated signaling pathways. Preclinical evidence substantiates their ability to enhance neurotrophin levels, particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), and activate their cognate Trk receptors. Activation of these pathways, including PI3K/AKT/mTOR and MAPK/ERK, converges on transcription factors such as CREB, promoting neuronal survival, neurite outgrowth, and synaptic plasticity. However, the precise molecular mechanisms linking these small molecules to the complex orchestration of neurotrophic gene expression remain incompletely defined. This review synthesizes current knowledge of the neurotrophic pharmacology of H. erinaceus bioactives and proposes a novel framework suggesting that non-coding RNAs (ncRNAs) play a key regulatory role. We hypothesize that hericenones and erinacines modulate key transcriptional hubs, such as CREB, Nrf2, and NF-κB, which in turn regulate the expression of specific ncRNAs (e.g., miR-132, miR-146a) known to control neurogenesis, synaptogenesis, oxidative stress, and neuroinflammation. This ncRNA-mediated mechanism may represent an un-explored axis that explains the pleiotropic neuroprotective effects of these compounds. We critically appraise the existing preclinical evidence, identify significant methodological limitations and translational gaps, and propose a structured research roadmap to test these ncRNA-centric hypotheses, aiming to accelerate the rational development of H. erinaceus-derived compounds for neurodegenerative diseases. Full article

Hypoxia–ischemia (HI)-related brain injury impacts millions of neonates worldwide. Male neonates are two times more susceptible to developing HI. We have previously reported that the administration of the neurotrophin receptor tyrosine kinase B (TrkB) agonist 7,8-dihydroxyflavone (DHF) following neonatal HI increases hippocampal TrkB phosphorylation and improves hippocampal-dependent learning and memory in early adult life only in females. We hypothesize that sex differences in HI outcomes are due to alterations in neonatal hippocampal steroid content, mainly the neural testosterone. At postnatal day 9, C57BL/6J mice underwent sham and Vannucci’s HI surgeries and were treated either with DHF or vehicle control. Hippocampi and plasma were collected on days 1 and 3 post-HI and liquid chromatography tandem mass spectrometry was used to determine the testosterone (T), estradiol (E₂), progesterone (P₄), and corticosterone (CORT) contents in these samples. All hippocampal steroid contents were at least 10-fold higher than in plasma, suggesting neural synthesis. Males had higher hippocampal T content than females at 3 days post-HI. Treatment with DHF reduced T in the female hippocampi at 3 days post-HI, but not in males. These findings suggest that the neuroprotective effect of DHF in females may be mediated, at least in part, through the reduction in hippocampal T following HI. Full article

Background/Objectives: Ischemic stroke is a leading cause of death and disability, and neuroprotection therapies, or those that increase recovery, are not available. While the garlic-derived bioactive compound S-allyl cysteine (SAC) has shown neuroprotective properties, its subacute long-term effects remain underexplored, particularly in females. Methods: We evaluated whether SAC supports functional recovery after ischemia/reperfusion (IR), focusing on neurotrophin signaling, tropomyosin receptor kinase B (TrkB), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK). Adult female Wistar rats underwent 1 h of ischemia and 15 days of reperfusion. SAC (100 mg/kg, i.p.) was administered at the onset of reperfusion and daily for 15 days. Motor and cognitive deficit tests were performed. Infarct area, Ki67, brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), pTrkB, pAKT, and pERK levels were quantified in the cortex, striatum, and hippocampus. Results: MicroPET analysis revealed comparable glucose uptake between the IR and IR + SAC groups, indicating similar ischemic severity. SAC reduced infarct area (54.7%) and significantly improved motor deficits (53.9%), circling behavior (38.9%), and long-term memory compared with ischemia/reperfusion (IR) animals. SAC increased the proportion of Ki67-positive cells (4.3-fold in the cortex and 1.8-fold in the striatum) and enhanced neurotrophin levels, NGF (cortex), BDNF (cortex and striatum), VEGF (striatum), pTrkB, pAKT, and pERK (cortex and striatum). Conclusions: SAC supports post-ischemic recovery, improving motor performance and preserving long-term recognition memory, effects that could be associated with increased cell proliferation, neurotrophin levels, and activation of the TrkB, AKT, and ERK pathways. Full article

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Scutellaria baicalensis, exhibits antioxidant, anti-inflammatory, and neuroprotective properties and has recently gained attention for its potential to improve cognitive deficits and mood disorders. In this study, we investigated baicalin’s antidepressant potential and its underlying mechanisms across multiple experimental levels. We found that oral administration of baicalin produced antidepressant-like effects in both naïve mice and those subjected to chronic restraint stress (CRS). CRS impaired hippocampal long-term potentiation (LTP), whereas baicalin restored these synaptic deficits. Importantly, intra-dorsal hippocampal microinjection of the TrkB receptor antagonist ANA-12 abolished baicalin’s antidepressant effects, indicating the involvement of BDNF–TrkB signaling. Baicalin also reduced reactive oxygen species (ROS)/H₂O₂ production in a BDNF-associated manner, demonstrating clear antioxidant activity. Molecular docking further suggested that baicalin binds more effectively to the TrkB receptor than ANA-12, supporting its capacity to activate TrkB-mediated signaling. By integrating in vivo, ex vivo, in vitro, and in silico approaches, our study shows that baicalin exerts robust antioxidant in vitro and antidepressant effects in vivo. These benefits are primarily mediated through activation of BDNF–TrkB signaling, leading to reduced ROS/H₂O₂ accumulation and alleviation of CRS-induced depression-like behaviors. Full article

Olive pomace (OP), a by-product of olive oil production, is a sustainable resource rich in bioactive compounds with potential applications in cosmetics and pharmaceuticals. This study investigates the protective effects of olive pomace juice (OPJ) against H₂O₂-induced neuronal damage and LPS-induced inflammatory responses in HT22 and BV2 cells, respectively. OPJ suppressed H₂O₂-induced cell death and exerted anti-apoptotic effects by reducing the BAX/BCL2 ratio and caspase-3 cleavage. OPJ also mitigated neurodegenerative hallmarks by decreasing amyloid fibrils formation and inhibiting β-secretase and acetylcholinesterase (AChE) activity. Mechanistically, OPJ enhanced antioxidant response by upregulating Nrf2 and its downstream molecule HO-1, along with increasing mRNA levels of antioxidant enzymes, including catalase, SOD1, and GPx. OPJ further activated AMPKα–SIRT1–PGC1α signaling and CREB–BDNF–TrkB signaling, suggesting modulation of key antioxidant, anti-apoptotic, and neurotrophic pathways. In BV2 cells, OPJ downregulated pro-inflammatory cytokines (IL-6 and IL-1β) and decreased iNOS and COX-2 expression through suppression of NF-κB and MAPK signaling pathways. HPLC analysis identified hydroxytyrosol (10.92%) as the major active compound in OPJ, which compared with tyrosol (2.18%), and hydroxytyrosol exhibited greater neuroprotective and anti-inflammatory effects than tyrosol. This study highlights the potential of OPJ and its major compound, hydroxytyrosol, as functional agents for mitigating neurodegeneration-related cellular response, supporting its application in the food and pharmaceutical industries. Full article

Brain-derived growth factor, BDNF, has critical roles in a wide variety of neuronal aspects, including cell survival, differentiation, and synaptic function after their maturation. TrkB, a high-affinity receptor for BDNF, is a major contributor in these neuronal aspects, and its functions are exerted via stimulating intracellular signaling pathways including the mitogen-activated protein kinase (MAPK) pathways. As a family of MAPKs, the functions of ERK1/2, p38MAPK, and JNKs have been extensively studied using in vivo and in vitro neuronal systems. ERK 1/2, a major serine-threonine kinase and belonging to the MAPK family, also works as a downstream molecule after activation of the BDNF/TrkB system. Interestingly, growing evidence has demonstrated that ERK1/2 signaling exerts a positive or negative influence on neurons in both healthy and pathological conditions in the central nervous system (CNS). Indeed, activation of ERK 1/2 stimulated by the BDNF/TrkB system is involved in the regulation of synaptic plasticity. On the other hand, overactivation of ERK1/2 signaling under pathological conditions is closely related to neurodegeneration. Furthermore, cell stress activates p38MAPKs and JNK signaling, contributing to the progression of neurodegeneration. In this review, we show how MAPK pathway signaling affects neuronal fate, including cell survival or cell death, in the CNS. Moreover, we discuss the involvement of overactivation of MAPK signaling in the neurodegeneration observed in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Full article

Neuroprotection represents a promising approach for mitigating retinal degeneration. Cord blood serum (CBS), rich in trophic factors such as the brain-derived neurotrophic factor (BDNF), has shown therapeutic potential for ocular surface diseases; however, its role in retinal neuroprotection remains underexplored. This study evaluates the protective effects of CBS on retinal pigment epithelium (ARPE-19) and photoreceptor-like (661W) cells exposed to oxidative stress. Cells were cultured in media supplemented with fetal bovine serum (FBS) or CBS with either high (CBS-H) or low (CBS-L) BDNF content. Oxidative stress was induced using hydrogen peroxide (H₂O₂), and cell viability was measured via an MTS assay. ZO-1 expression was analyzed in ARPE-19 cells to assess tight junction integrity, while mitochondrial function in 661W cells was examined using MitoRed staining. TrkB receptor involvement was investigated using the inhibitor K252a and Western blot analysis. CBS significantly improved cell viability under oxidative conditions. CBS-H increased ZO-1 expression in ARPE-19 cells, indicating preserved epithelial integrity. In 661W cells, CBS maintained mitochondrial integrity and enhanced TrkB phosphorylation, while TrkB inhibition reduced its protective effect. These findings indicate that CBS confers neuroprotection through BDNF-TrkB signaling together with other trophic factors, supporting its potential as a multifactorial therapeutic strategy for retinal degeneration that deserves further exploration. Full article

Huntington’s Disease (HD) is characterized by prominent degeneration of the principal neurons of the striatum and by progressive motor and cognitive deterioration. Striatal neurons degenerate in HD due to multiple cell-autonomous and non-autonomous factors. Impaired neurotrophin signaling by brain-derived neurotrophic factor (BDNF) and its cognate receptor Tropomyosin receptor kinase B (TrkB) is an important mechanism underlying neuronal loss in HD. Fingolimod, a clinically approved oral drug for Multiple Sclerosis, was originally developed based on its anti-inflammatory properties. Recent work suggests that fingolimod can also promote BDNF expression and enhance neurotrophic support in the brain. We hypothesized that fingolimod treatment initiated during the presymptomatic phase would increase striatal BDNF levels and protect against motor dysfunction in HD. In wild-type mice, fingolimod treatment increases striatal BDNF levels and enhances BDNF-TrkB signaling. However, chronic fingolimod therapy (0.1 mg/kg, i.p., twice per week, over 7 weeks) initiated at age 4 weeks in the R6/2 mouse model of HD failed to improve behavioral locomotor deficits and exacerbated limb clasping. Furthermore, fingolimod treatment in these presymptomatic R6/2 mice acutely decreased BDNF-TrkB signaling in the striatum in a dose-dependent manner. In contrast, acute administration of fingolimod in symptomatic 7-week-old R6/2 mice increased striatal BDNF-TrkB signaling in a dose-dependent manner, consistent with previous work suggesting that chronic fingolimod can improve motor behavior when given during the symptomatic phase. Thus, the effects of fingolimod striatal BDNF-TrkB signaling and motor behavior in HD are complex and vary with disease stage. Addressing this variability is critical for the design of neuroprotective drug trials in HD, including those utilizing sphingosine-1-phosphate receptor (S1P) modulators. Full article

Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Areca catechu L., displays diverse neuropharmacological properties, yet its role in stress-induced emotional dysfunction has not been fully elucidated. This study examined the anxiolytic-like and neuroprotective effects of arecoline in mice exposed to chronic unpredictable mild stress (CUMS). Arecoline administration markedly improved behavioral outcomes, reflected by increased central exploration in the open-field test, prolonged time in the light compartment, and enhanced open-arm activity in the elevated plus maze. These behavioral benefits were accompanied by normalization of serum corticosterone levels, restoration of hippocampal neurotransmitters, reinforcement of antioxidant enzyme activities, and attenuation of pro-inflammatory cytokines. At the molecular level, arecoline elevated brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), cAMP response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR), and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), indicating enhanced synaptic plasticity, while concurrently diminishing oxidative and inflammatory stress. Collectively, the findings suggest that arecoline exerts multifaceted neuroprotective actions under chronic stress by coordinating neuroendocrine modulation, neurotransmitter homeostasis, antioxidant defenses, and synaptic plasticity. This study provides new mechanistic evidence supporting the potential relevance of arecoline as a functional neuroactive compound for managing stress-induced anxiety disorders. Full article