Neurotrophic Factor Growth Research Articles

SerpinA3N Regulates the Secretory Phenotype of Mouse Senescent Astrocytes Contributing to Neurodegeneration.

Senescent astrocyte accumulation in the brain during normal aging is a driver of age-related neurodegenerative diseases such as Alzheimer's disease. However, the molecular events underlying astrocyte senescence in Alzheimer's disease are not fully understood. In this study, we demonstrated that senescent astrocytes display a secretory phenotype known as the senescence-associated secretory phenotype (SASP), which is associated with the upregulation of various proinflammatory factors and the downregulation of neurotrophic growth factors (eg, NGF and BDNF), resulting in a decrease in astrocyte-mediated neuroprotection and increased risk of neurodegeneration. We found that SerpinA3N is upregulated in senescent primary mouse astrocytes after serial passaging in vitro or by H2O2 treatment. Further exploration of the underlying mechanism revealed that SerpinA3N deficiency protects against senescent astrocyte-induced neurodegeneration by suppressing SASP-related factors and inducing neurotrophic growth factors. Brain tissues from Alzheimer's disease model mice possessed increased numbers of senescent astrocytes. Moreover, senescent astrocytes exhibited upregulated SerpinA3N expression in vitro and in vivo, confirming that our cell model recapitulated the in vivo pathology of these neurodegenerative diseases. Altogether, our study reveals a novel molecular strategy to regulate the secretory phenotype of senescent astrocytes and implies that SerpinA3N and its regulatory mechanisms may be potential targets for delaying brain aging and aging-related neurodegenerative diseases.

Growth factors PDGF-AA, PDGF-BB and BDNF as potential differentiating biomarkers of unipolar and bipolar depression

To establish the differences and identify the prognostic value of biological markers - platelet growth factors PDGF-AA, PDGF-BB and brain-derived neurotrophic growth factor (BDNF) - for the differential diagnosis of patients with unipolar and bipolar depression using machine learning. The study included 79 patients aged 48 [34; 57] years, including 35 people with bipolar depression (ICD-10. F31) and 44 people with unipolar depression (F32-33). Clinical assessment of the patients' condition was carried out using the Hamilton Depression Rating Scale (HDRS-17) and the Hamilton Anxiety Rating Scale (HARS). The concentration of growth factors in the blood serum of patients was determined using multiplex analyzers Magpix and Luminex 200 (Luminex, USA). To build a predictive model, the support vector machine was used. Patients with bipolar depression showed statistically significant higher concentrations of PDGF-AA and PDGF-BB, as well as lower concentrations of BDNF. When constructing a predictive model, it was possible to separate patients with unipolar and bipolar depression according to all three biomarkers; the sensitivity and specificity of the model were 0.96±0.06 and 0.95±0.05, respectively. The study of concentrations of BDNF and platelet-derived growth factors shows statistically significant differences in indicators in the case of unipolar and bipolar depression, which can potentially be used as prognostic biomarkers for differential diagnosis in appropriate clinical cases.

Olfactory neuronal precursors as a model to analyze the effects of melatonin in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder of great importance affecting millions globally and its prevalence will triple in the following decades. Therefore, analysis and identification of substances which can effectively reduce the pathological process of this disease in different study models are crucial. Melatonin works as a multitasking substance and some of its activities could be used to target the neurodegenerative process of AD. These include, but not limited to, its potent antioxidant activity, regulation of sleep-wake rhythms (important for the consolidation of memory and cognition) and its action as a neurotrophic growth factor that promotes differentiation and neuronal proliferation. To evaluate the effects of melatonin at cellular level in AD, it is essential to have a study model that reflects the pathological process occurring in the CNS. In this, review we summarize the potential use of olfactory neuronal precursors derived from olfactory neuroepithelium directly obtained from patients for such purposes.

Abstract C056: Characterization of prostate cancer secretomes for therapeutic intervention

Abstract Introduction: Prostate cancer (PC) is a common malignancy among men, often driven by dysregulated androgen receptor (AR) signaling. Earlier stages of PC can be favorably treated with androgen deprivation therapies or AR signaling inhibitors. Unfortunately, metastatic PC (mPC) is currently incurable. Neuroendocrine prostate cancer (NEPC) is a subgroup of mPC that may be derived as result of transdifferentiation of adenocarcinomas, after AR-directed treatment. Previous studies using preclinical models have suggested a potentially beneficial relationship between NEPC and AR-active prostate cancer (ARPC) cells. We hypothesize that secreted factors derived from NEPC cells influence local, and distant ARPC cell types to promote treatment resistance. Methods: Five NEPC in vitro cell models: NCI-H660, MSKCC-EF1, LTL331R, LuCaP-49 and LuCaP-173.1 were maintained in serum free media for 24 hours. The conditioned media (CM) was then collected and admixed with growth medium for ARPC cells. The ARPC growth medium was either supplemented with Fetal Bovine Serum (FBS) or Charcoal Stripped fetal bovine Serum (CSS). GFP-labelled ARPC cells: LnCaP and C42B were seeded in the respective media admixed with the CM. The viability of cells was measured using a Cytation5 microplate reader. We implemented a transcriptomic (RNAseq) and mass-spectrometry based proteomic analysis to identify differentially expressing secretory proteins that could have an impact on the treatment resistance of ARPC cell types. Results: All 5 NEPC-CM showed qualitative growth promoting effects towards ARPC C42B cells grown in CSS supplemented media. Only CM from EF1 and H660 promoted the growth of ARPC C42B in FBS supplemented media. NEPC-CM did not affect growth of LnCaP ARPC cells. Mass-spectrometry for secreted proteins was performed on 3 NEPC cell models. Analysis of the proteins against the PANTHER gene ontology database shows: (i) cell communication, and (ii) cellular response to stimulus, as two important biological processes active in NEPC. Genes involved in the two pathways were further compared against a comprehensive transcriptomic dataset spanning distinct mPC phenotypes and genotypes. Neurotrophic growth factors: Brain-derived growth factor (BDNF), Nerve-growth factor (NGF), VGF and neurotrophin-3 (NT-3) emerged as important targets that were differentially expressed in NEPC versus ARPC cells. Conclusions: NEPC cells have the potential to influence ARPC phenotypes that include enhanced proliferation, AR targeting, and potentially other drug resistance programs. As mPC exhibits substantial intra-individual and intra-tumor heterogeneity, understanding a targeting heterotypic cell interactions could lead to new druggable targets and address treatment resistance resulting from complex inter-cellular interactions. (Funding: PC220408) Citation Format: Tarana Arman, Lisa A. Jones, Ilsa M. Coleman, Philip R. Gafken, Peter S. Nelson. Characterization of prostate cancer secretomes for therapeutic intervention [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C056.

Mechanisms of Wharton’s Jelly-derived MSCs in enhancing peripheral nerve regeneration

Warton’s jelly-derived Mesenchymal stem cells (WJ-MSCs) play key roles in improving nerve regeneration in acellular nerve grafts (ANGs); however, the mechanism of WJ-MSCs-related nerve regeneration remains unclear. This study investigated how WJ-MSCs contribute to peripheral nerve regeneration by examining immunomodulatory and paracrine effects, and differentiation potential. To this end, WJ-MSCs were isolated from umbilical cords, and ANGs (control) or WJ-MSCs-loaded ANGs (WJ-MSCs group) were transplanted in injury animal model. Functional recovery was evaluated by ankle angle and tetanic force measurements up to 16 weeks post-surgery. Tissue biopsies at 3, 7, and 14 days post-transplantation were used to analyze macrophage markers and interleukin (IL) levels, paracrine effects, and MSC differentiation potential by quantitative real-time polymerase chain reaction (RT-qPCR) and immunofluorescence staining. The WJ-MSCs group showed significantly higher ankle angle at 4 weeks and higher isometric tetanic force at 16 weeks, and increased expression of CD206 and IL10 at 7 or 14 days than the control group. Increased levels of neurotrophic and vascular growth factors were observed at 14 days. The WJ-MSCs group showed higher expression levels of S100β; however, the co-staining of human nuclei was faint. This study demonstrates that WJ-MSCs' immunomodulation and paracrine actions contribute to peripheral nerve regeneration more than their differentiation potential.

The role of midkine in health and disease.

Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration, angiogenesis, reproduction, and repair. Recent research has indicated that MDK functions as a key player in autoimmune disorders of the central nervous system (CNS), such as Multiple Sclerosis (MS) and is a promising therapeutic target for the treatment of brain tumors, acute injuries, and other CNS disorders. This review summarizes the modes of action and immunological functions of MDK both in the peripheral immune compartment and in the CNS, particularly in the context of traumatic brain injury, brain tumors, neuroinflammation, and neurodegeneration. Moreover, we discuss the role of MDK as a central mediator of neuro-immune crosstalk, focusing on the interactions between CNS-infiltrating and -resident cells such as astrocytes, microglia, and oligodendrocytes. Finally, we highlight the therapeutic potential of MDK and discuss potential therapeutic approaches for the treatment of neurological disorders.

Hypothermia combined with extracellular vesicles from clonally expanded immortalized mesenchymal stromal cells improves neurodevelopmental impairment in neonatal hypoxic-ischemic brain injury

BackgroundNeonatal encephalopathy following hypoxia–ischemia (HI) is a leading cause of childhood death and morbidity. Hypothermia (HT), the only available but obligatory therapy is limited due to a short therapeutic window and limited efficacy. An adjuvant therapy overcoming limitations of HT is still missing. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have shown promising therapeutic effects in various brain injury models. Challenges associated with MSCs’ heterogeneity and senescence can be mitigated by the use of EVs from clonally expanded immortalized MSCs (ciMSCs). In the present study, we hypothesized that intranasal ciMSC-EV delivery overcomes limitations of HT.MethodsNine-day-old C57BL/6 mice were exposed to HI by occlusion of the right common carotid artery followed by 1 h hypoxia (10% oxygen). HT was initiated immediately after insult for 4 h. Control animals were kept at physiological body core temperatures. ciMSC-EVs or vehicle were administered intranasally 1, 3 and 5 days post HI/HT. Neuronal cell loss, inflammatory and regenerative responses were assessed via immunohistochemistry, western blot and real-time PCR 7 days after insult. Long-term neurodevelopmental outcome was evaluated by analyses of cognitive function, activity and anxiety-related behavior 5 weeks after HI/HT.ResultsIn contrast to HT monotherapy, the additional intranasal therapy with ciMSC-EVs prevented HI-induced cognitive deficits, hyperactivity and alterations of anxiety-related behavior at adolescence. This was preceded by reduction of striatal neuronal loss, decreased endothelial, microglia and astrocyte activation; reduced expression of pro-inflammatory and increased expression of anti-inflammatory cytokines. Furthermore, the combination of HT with intranasal ciMSC-EV delivery promoted regenerative and neurodevelopmental processes, including endothelial proliferation, neurotrophic growth factor expression and oligodendrocyte maturation, which were not altered by HT monotherapy.ConclusionIntranasal delivery of ciMSC-EVs represents a novel adjunct therapy, overcoming limitations of acute HT thereby offering new possibilities for improving long-term outcomes in neonates with HI-induced brain injury.

Evaluation of Cognitive and Biochemical Brain Status in Patients after Carotid Endarterectomy

INTRODUCTION: In the large studies such as NASCET, ESCT, VACS, ACAS and ACST-1, the role of alteration of the cognitive functions of a patient in the early and long-term postoperative periods have not been determined.
 AIM: To evaluate the biochemical parameters of cerebral functions, the cognitive status of patients, and their interrelation after carotid endarterectomy.
 MATERIALS AND METHODS: The study involved 60 patients divided into two groups. The mean age was 67.3 ± 7.9 years, there were 49 (81%) men and 19 (19%) women. Group A included ‘symptomatic’ patients (n = 30) who underwent carotid endarterectomy and had a history of an acute cerebrovascular event. Group B included ‘asymptomatic’ patients (n = 30) who underwent carotid endarterectomy but had no history of cerebrovascular events. As part of the study, the following data were evaluated within a 6-month period: cognitive status (on MMSE, FAB, MoCA-test, NIHSS scales), biochemical parameters (S100b protein, neuron specific enolase (NSE), brain derived neurotrophic growth factor (BDNF)) and the ultrasound data of the carotid arteries.
 RESULTS: Patients of group A showed improvement of the cognitive status by the 6th month on MMSE scale (p = 0.001) and in MoCA-test (p = 0.09) relative to the initial parameters; on FAB scale relative to the data after 1 month (p = 0.01); a decline of the level of neurological deficit on NIHSS scale (p = 0.01). In group A, an inverse correlation was found between the results on MMSE scale and resistance index (r = -0.675; p = 0.005), and a direct correlation between the results on FAB scale and the end diastolic pressure in the internal carotid artery (r = +0.912; p = 0.005) according to the ultrasound data. The data obtained in group B, reflected improvement of the cognitive status by the 6th month only by 2 points on MoCA test (p = 0. 03) relative to the initial data. Besides, in 6 months after the surgery, there was a 2-fold increase in S100b marker (p = 0.01) and NSE protein (p = 0.02) and a 1.5-fold increase in BDNF protein as compared to the initial values (p = 0.005).
 CONCLUSIONS: Carotid endarterectomy leads to improvement of the cognitive status evaluated on MMSE, FAB, MoCA, NIHSS scales in the long-term postoperative period in symptomatic patients. The extent of improvement of neuropsychological status depends on the level of the end diastolic pressure and resistance index in the internal carotid artery on the operated side.

A review focus on the latest research progress of vitamin D in brain science

Vitamin D is a hormone precursor that is increasingly recognized for its broad impact, including on brain health. Vitamin D regulates neurotrophic growth factors and influences inflammation and thrombosis; all of which affect neurocognition. Lack of vitamin D can cause osteoporosis, decreased bone density, and fractures. The flesh of fatty fish and fish liver oils are the finest sources of vitamin D. Any mixture of calcifediol, obtained from vitamin D3, and ercalcidiol, derived from vitamin D2, is known as 25-hydroxyvitamin D, also known as 25(OH)D. Loss of cognitive abilities including thinking, remembering, and reasoning is referred to as dementia. Some dementia patients have emotional instability and personality changes. The most common type of dementia is Alzheimer's disease. The condition is gradual, starting with minor memory loss and potentially progressing to the loss of communication and environmental awareness. One of the characteristics of Alzheimer's disease, amyloid beta (Aβ) aggregates, are known to be cleared by vitamin D. Additionally, vitamin D may offer neuroprotection against tau hyperphosphorylation brought on by A. As a result, dementia and Alzheimer's disease are more likely to develop in those with low vitamin D levels. A stroke, also known as a brain attack, happens when a blood artery in the brain breaks or when something stops the flow of blood to a specific area of the brain. Parts of the brain suffer harm or degeneration in either scenario. In addition, the risk of stroke may be raised by vitamin D deficiency.

The Role of JNK and p53 in the Regulation of Secretory Function of Neuroglial Cells of Various Types in β-Amyloid-Induced Neurodegeneration.

We studied the effect of JNK and p53 inhibitors on the production of neurotrophic factors stimulating the realization of the growth potential of neural stem cells by neuroglial cells of various types under conditions of simulation of induced β-amyloid neurodegeneration in vitro. It was shown that β-amyloid stimulates the production of neurotrophins by astrocytes and microglial cells, but does not affect the functioning of oligodendrocytes. JNK and p53 were not involved in the secretion of neurotrophins by intact astrocytes. The stimulating role of p53 on the implementation of their secretory activity under the influence of a neurotoxic agent was revealed. At the same time, the inhibitory role of JNK and p53 in the production of neurotrophic growth factors by oligodendrocytes and microglial cells was revealed both under conditions of their optimal vital activity and when β-amyloid was added to the cell culture.

Fucosyltransferase 9 promotes neuronal differentiation and functional recovery after spinal cord injury by suppressing the activation of Notch signaling.

Individuals with spinal cord injury (SCI) suffer from permanent disabilities such as severe motor, sensory and autonomic dysfunction. Neural stem cell transplantation has proven to be a potential strategy to promote regeneration of the spinal cord, since NSCs can produce neurotrophic growth factors and differentiate into mature neurons to reconstruct the injured site. However, it is necessary to optimize the differentiation of NSCs before transplantation to achieve a better regenerative outcome. Inhibition of Notch signaling leads to a transition from NSCs to neurons, while the underlying mechanism remains inadequately understood. Our results demonstrate that overexpression of fucosyltransferase 9 (Fut9), which is upregulated by Wnt4, promotes neuronal differentiation by suppressing the activation of Notch signaling through disruption of furin-like enzyme activity during S1 cleavage. In an in vivo study, Fut9-modified NSCs efficiently differentiates into neurons to promote functional and histological recovery after SCI. Our research provides insight into the mechanisms of Notch signaling and a potential treatment strategy for SCI.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer's disease.

Recent studies have demonstrated that neuroplasticity, such as synaptic plasticity and neurogenesis, exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer's disease. Hence, promoting neuroplasticity may represent an effective strategy with which Alzheimer's disease can be alleviated. Due to their significant ability to self-renew, differentiate, and migrate, neural stem cells play an essential role in reversing synaptic and neuronal damage, reducing the pathology of Alzheimer's disease, including amyloid-β, tau protein, and neuroinflammation, and secreting neurotrophic factors and growth factors that are related to plasticity. These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain. Consequently, neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer's disease and other neurodegenerative diseases. In this review, we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer's disease in the clinic.

Novel Phenylethanoid Glycosides Improve Hippocampal Synaptic Plasticity via the Cyclic Adenosine Monophosphate-CREB-Brain-Derived Neurotrophic Growth Factor Pathway in APP/PS1 Transgenic Mice

Introduction: Alzheimer’s disease (AD) is a major public health concern worldwide, but there are still no drugs available that treat it effectively. Previous studies have shown that phenylethanoid glycosides have pharmacological effects, which include anti-AD properties, but the underlying mechanisms by which they ameliorate AD symptoms remain unknown. Methods: In this study, we used an APP/PS1 AD mouse model to explore the function and mechanisms underlying savatiside A (SA) and torenoside B (TB) in the treatment of AD. SA or TB (100 mg·kg-1·d-1) was orally administered to 7-month-old APP/PS1 mice for 4 weeks. Cognitive and memory functions were measured using behavioral experiments (including the Morris water maze test and the Y-maze spontaneous alternation test). Molecular biology experiments (including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays) were used to detect any corresponding changes in signaling pathways. Results: The results showed that SA or TB treatment could significantly reduce cognitive impairment in APP/PS1 mice. We also showed that chronic treatment with SA/TB could prevent spine loss, synaptophysin immunoreactivity, and neuronal loss in mice, thereby improving synaptic plasticity and moderating learning and memory deficits. SA/TB administration also promoted the expression of synaptic proteins in APP/PS1 mouse brains and upregulated phosphorylation of proteins in the cyclic adenosine monophosphate (cAMP)/CREB/brain-derived neurotrophic growth factor (BDNF) pathway that are responsible for synaptic plasticity. Additionally, chronic SA/TB treatment increased the levels of BDNF and nerve growth factor (NGF) in the brains of APP/PS1 mice. Both astrocyte and microglia volumes, as well as the generation of amyloid β, were also decreased in SA/TB-treated APP/PS1 mice compared to control APP/PS1 mice. Conclusion: In summary, SA/TB treatment was associated with activation of the cAMP/CREB/BDNF pathway and increased BDNF and NGF expression, indicating that SA/TB improves cognitive functioning via nerve regeneration. SA/TB is a promising candidate drug for the treatment of AD.

Building better brains: the pleiotropic function of neurotrophic factors in postnatal cerebellar development.

The cerebellum is a multifunctional brain region that controls diverse motor and non-motor behaviors. As a result, impairments in the cerebellar architecture and circuitry lead to a vast array of neuropsychiatric and neurodevelopmental disorders. Neurotrophins and neurotrophic growth factors play essential roles in the development as well as maintenance of the central and peripheral nervous system which is crucial for normal brain function. Their timely expression throughout embryonic and postnatal stages is important for promoting growth and survival of both neurons and glial cells. During postnatal development, the cerebellum undergoes changes in its cellular organization, which is regulated by a variety of molecular factors, including neurotrophic factors. Studies have shown that these factors and their receptors promote proper formation of the cerebellar cytoarchitecture as well as maintenance of the cerebellar circuits. In this review, we will summarize what is known on the neurotrophic factors' role in cerebellar postnatal development and how their dysregulation assists in developing various neurological disorders. Understanding the expression patterns and signaling mechanisms of these factors and their receptors is crucial for elucidating their function within the cerebellum and for developing therapeutic strategies for cerebellar-related disorders.

Biological Evaluation of Graphene Quantum Dots and Nitrogen-Doped Graphene Quantum Dots as Neurotrophic Agents.

Over time, developments in nano-biomedical research have led to the creation of a number of systems to cure serious illnesses. Tandem use of nano-theragnostics such as diagnostic and therapeutic approaches tailored to the individual disease treatment is crucial for further development in the field of biomedical advancements. Graphene has garnered attention in the recent times as a potential nanomaterial for tissue engineering and regenerative medicines owing to its biocompatibility among the several other unique properties it possesses. The zero-dimensional graphene quantum dots (GQDs) and their nitrogen-doped variant, nitrogen-doped GQDs (N-GQDs), have good biocompatibility, and optical and physicochemical properties. GQDs have been extensively researched owing to several factors such as their size, surface charge, and interactions with other molecules found in biological media. This work briefly elucidates the potential of electroactive GQDs as well as N-GQDs as neurotrophic agents. In vitro investigations employing the N2A cell line were used to evaluate the effectiveness of GQDs and N-GQDs as neurotrophic agents, wherein basic investigations such as SRB assay and neurite outgrowth assay were performed. The results inferred from immunohistochemistry followed by confocal imaging studies as well as quantitative real-time PCR (qPCR) studies corroborated those obtained from neurite outgrowth assay. We have also conducted a preliminary investigation of the pattern of gene expression for neurotrophic and gliotrophic growth factors using ex vivo neuronal and mixed glial cultures taken from the brains of postnatal day 2 mice pups. Overall, the studies indicated that GQDs and N-GQDs hold prospect as a framework for further development of neuroactive compounds for relevant central nervous system (CNS) purposes.

Hepatocyte growth factor mimetic confers protection from aminoglycoside-induced hair cell death in vitro

Loss of sensory hair cells from exposure to certain licit drugs, such as aminoglycoside antibiotics, can result in permanent hearing damage. Exogenous application of the neurotrophic molecule hepatocyte growth factor (HGF) promotes neuronal cell survival in a variety of contexts, including protecting hair cells from aminoglycoside ototoxicity. HGF itself is not an ideal therapeutic due to a short half-life and limited blood-brain barrier permeability. MM-201 is a chemically stable, blood-brain barrier permeable, synthetic HGF mimetic that serves as a functional ligand to activate the HGF receptor and its downstream signaling cascade. We previously demonstrated that MM-201 robustly protects zebrafish lateral line hair cells from aminoglycoside ototoxicity. Here, we examined the ability of MM-201 to protect mammalian sensory hair cells from aminoglycoside damage to further evaluate MM-201’s clinical potential. We found that MM-201 exhibited dose-dependent protection from neomycin and gentamicin ototoxicity in mature mouse utricular explants. MM-201’s protection was reduced following inhibition of mTOR, a downstream target of HGF receptor activation, implicating the activation of endogenous intracellular substrates by MM-201 as critical for the observed protection. We then asked if MM-201 altered the bactericidal properties of aminoglycosides. Using either plate or liquid growth assays we found that MM-201 did not alter the bactericidal efficacy of aminoglycoside antibiotics at therapeutically relevant concentrations. We therefore assessed the protective capacity of MM-201 in an in vivo mouse model of kanamycin ototoxicity. In contrast to our in vitro data, MM-201 did not attenuate kanamycin ototoxicity in vivo. Further, we found that MM-201 was ototoxic to mice across the dose range tested here. These data suggest species- and tissue-specific differences in otoprotective capacity. Next generation HGF mimetics are in clinical trials for neurodegenerative diseases and show excellent safety profiles, but neither preclinical studies nor clinical trials have examined hearing loss as a potential consequence of pharmaceutical HGF activation. Further research is needed to determine the consequences of systemic MM-201 application on the auditory system.

Does increasing insulin resistance in adolescence actively decrease cerebral perfusion to oral glucose tolerance test?

Background: Approximately 20% of American adolescents are obese, and nearly half demonstrate some form of insulin resistance (IR). Insulin acts as a metabolic hormone, a neurotrophic growth factor, and a vasodilator. Notably, adults with neurologic disease often exhibit IR and reduced cerebral blood flow (CBF). Adolescent brains are actively growing such that IR may negatively impact brain health in part due to lower brain perfusion. Specifically, given the role of insulin as a potential vasodilator, we hypothesized CBF would increase in response to a physiologic glucose-insulin surge, but this effect would lessen as IR level increased. Methods: Adolescents (n=11, 3 females, age=14.8±2 yr, BMI=24.7±7) taking no medications were studied. IR was estimated by calculating HOMA-IR using fasting glucose and insulin, spanning a spectrum of IR (excluding diabetes). Subjects completed a magnetic resonance imaging (MRI) study visit to assess cerebral perfusion using arterial spin labeling (ASL). Heart rate (HR), mean arterial pressure (MAP) and end tidal CO 2 (ETCO 2 ) were assessed at baseline and during oral glucose tolerance test (OGTT); ingesting 75g glucose in 296mL water (Trutol). Venous blood was sampled at baseline and 5, 10, 20, 30, 45, and 60 minutes post OGTT. Perfusion at peak plasma insulin was compared to baseline. Significance was determined using linear regression of change in perfusion (peak- baseline) versus HOMA-IR and set at p≤0.05. Results: Results are mean±SD. HR (p=0.9), MAP (p=0.22) and ETCO 2 (p=0.75) were similar across HOMA-IR. MAP (p=0.44) and ETCO 2 (p=0.15) did not change during OGTT at insulin peak. Peak insulin occurred at 44±13 min post OGTT (baseline: 8±4 vs. peak: 65±38 μU/mL, p=0.001). Glucose changed from 79±6 to 142±30 mg/dL at peak insulin (p=0.0005). There were no significant associations between HOMA-IR and changes in perfusion in gray matter (R 2 =0.06, p=0.43) and white matter (R 2 =0.07, p=0.13). There were no significant associations for the following regions: hippocampus, amygdala, thalamus, anterior and posterior insula, and precuneus (R 2 all <0.2, p all >0.14). There was a trend toward negative regression in anterior cingulate gyrus (R 2 =0.25, p=0.11). Conclusions: These data suggest an OGTT does not acutely change brain perfusion at a global or regional level in adolescents, except possibly the anterior cingulate gyrus that is negatively impacted by increasing IR. The majority of present findings do not support our hypothesis that OGTT-mediated changes in cerebral perfusion are associated with IR in adolescents. NIH R21HD097510 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of increasing insulin resistance on cerebral perfusion in adolescents

Background: Adolescence is a key growth period that heavily influences future brain health. Approximately 1 in 5 adolescents are obese in the US, and up to half of them exhibit some form of insulin resistance (IR). Notably, insulin acts as a metabolic hormone, a neurotrophic growth factor, and a vasodilator. Reduced vasodilation may lead to reduced cerebral perfusion, and lower perfusion in older adults is associated with reduced cognition and increased risk of stroke and neurologic disease. Given this background, IR may negatively impact adolescent brain health in part due to lower brain perfusion. Therefore, we hypothesized cerebral perfusion would decrease as the level of insulin resistance increased. Method s: Adolescents (n=15, 4 females, age 15±2 yr) were studied. IR was estimated by calculating HOMA-IR (using fasting glucose and insulin), which spanned a spectrum of IR up to but excluding diabetes. Subjects underwent a magnetic resonance imaging (MRI) study visit to assess cerebral perfusion using arterial spin labeling (ASL). The CAT12 toolbox extension for SPM12 was used to process MRI data. Heart rate (HR), mean arterial pressure (MAP), and end tidal CO 2 (ETCO 2 ) were assessed. Significance was determined using linear regression and set at p≤0.05. Results: Results are mean±SD. HR (72±10 bpm, p=0.98), MAP (73±6 mmHg, p=0.67), and ETCO 2 (37±2 mmHg, p=0.91) were similar across HOMA-IR (0.5 to 3.8). Perfusion (ml/100g/min) at the amygdala (r 2 =0.33, p=0.02) and parahippocampal gyrus (r 2 =0.28, p=0.04) decreased as HOMA-IR increased. Borderline significant decreases were found for total gray matter (r 2 =0.26, p=0.051), anterior cingulate cortex (r 2 =0.26, p=0.052), and hippocampus (r 2 =0.23, p=0.07) perfusion as HOMA-IR increased. No associations were found between HOMA-IR and the following: total white matter (r 2 =0.18, p=0.11), precuneus (r 2 =0.20, p=0.10), thalamus proper (r 2 =0.14, p=0.17), and entorhinal cortex (r 2 =0.16, p=0.14) perfusion. Total gray matter (p=0.49) and white matter (p=0.73) volume had no significant relationship with HOMA-IR. HOMA-IR was not associated with any differences in regional volumes. Conclusions: Our results suggest with increasing HOMA-IR there is a significant reduction in gray matter perfusion in key brain regions associated with memory in adolescents. In contrast, structural changes were not detected, indicating functional decrements occur prior to structural deficits. These findings support our hypothesis that cerebral perfusion is associated with insulin resistance in adolescents, which may negatively impact long-term brain health. NIH R21 HD097510 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Participation of cAMP-Mediated Signaling Transduction in the Regulation of the Secretory Function of Neuroglia during Ethanol-Induced Neurodegeneration.

We studied the involvement of cAMP and PKA in the regulation of the secretion of neurotrophic growth factors by macro-and microglial cells in the model of ethanol-induced neurodegeneration in vitro and in vivo. The stimulating role of cAMP in the secretion of neurotrophins by intact astrocytes and oligodendrocytes was shown, while PKA does not participate in this process. On the contrary, the inhibitory role of cAMP (implemented via PKA activation) in the production of neurogenesis stimulators by microglial cells under conditions of optimal vital activity was found. Under the influence of ethanol, the role of cAMP and PKA in the production of growth factors by macroglial cells was considerably changed. The involvement of PKA in the cAMP-dependent signaling pathways and inversion of the role of this signaling pathway in the implementation of the neurotrophic secretory function of astrocytes and oligodendrocytes, respectively, directly exposed to ethanol in vitro were noted. Long-term exposure of the nervous tissue to ethanol in vivo led to the loss of the stimulating role of cAMP/PKA signaling on neurotrophin secretion by macroglial cells without affecting its inhibitory role in the regulation of this function in microglial cells.

Improving Schwann Cell Differentiation from Human Adipose Stem Cells with Metabolic Glycoengineering.

Schwann cells (SCs) are myelinating cells that promote peripheral nerve regeneration. When nerve lesions form, SCs are destroyed, ultimately hindering nerve repair. The difficulty in treating nerve repair is exacerbated due to SC's limited and slow expansion capacity. Therapeutic use of adipose-derived stem cells (ASCs) is emerging in combating peripheral nerve injury due to these cells' SC differentiation capability and can be harvested easily in large numbers. Despite ASC's therapeutic potential, their transdifferentiation period typically takes more than two weeks. In this study, we demonstrate that metabolic glycoengineering (MGE) technology enhances ASC differentiation into SCs. Specifically, the sugar analog Ac5ManNTProp (TProp), which modulates cell surface sialylation, significantly improved ASC differentiation with upregulated SC protein S100β and p75NGFR expression and elevated the neurotrophic factors nerve growth factor beta (NGFβ) and glial cell-line-derived neurotrophic factor (GDNF). TProp treatment remarkably reduced the SC transdifferentiation period from about two weeks to two days in vitro, which has the potential to improve neuronal regeneration and facilitate future use of ASCs in regenerative medicine.