Biology subjects

Park, K. D.

Publications and source records attributed to Park, K. D..

9 recordsLinked to original sources

bioRxiv2025

H2O2-induced astrocytic collagen triggers neuronal death via fucosylation-dependent glial barrier formation upon ischemic stroke

The cascade of molecular and cellular events leading to neuronal death after a focal ischemic stroke remains enigmatic. Although astrocytes form glial barriers that may protect surrounding tissue, how barriers develop and contribute to neuronal death is unclear. Here, we show that H2O2 induces astrocytic type I collagen (COL1)-production via miR-29-mediated post-transcriptional and fucosylation-dependent post-translational regulations, leading to integrin activation and neuronal death. In photothrombosis (PT)-induced cortical stroke model, PT triggered H2O2-surge, astrogliosis, glial barrier formation, COL1 expression, fibrotic scarring, altered N-glycosylation, neuronal loss, and neurological deficits. Remarkably, these effects were reversed by astrocyte-specific COL1 or FUT8 gene-silencing or treatment with KDS12025, an H2O2-decomposing peroxidase enhancer. KDS12025s neuroprotective effects were also recapitulated in non-human primate stroke model. These findings delineate a previously unrecognized astrocyte-driven mechanism in which oxidative stress induces COL1 production, promoting neuronal death, and position H2O2 and astrocytic COL1 and FUT8 as promising therapeutic targets for ischemic stroke.

neuroscience↗

bioRxiv2025

Astrocytic MAOB-GABA axis as a molecular brake on repair following spinal cord injury

Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system (CNS) injury. The glial scar has been proposed as a major contributor to this failure in the regenerative process. However, its underlying molecular and cellular mechanisms remain unclear. Here, we report that monoamine oxidase B (MAOB)-dependent excessive GABA release from reactive astrocytes suppresses CNS repair system by reducing BDNF and TrkB expression in severe spinal cord injury (SCI) animal models. Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery. Notably, the selective MAOB inhibitor, KDS2010, facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model. Its dose-dependent effects were further validated in a monkey SCI model. Moreover, KDS2010 demonstrates a tolerable safety profile and dose-proportional pharmacokinetics in healthy humans during a phase 1 clinical trial. Our findings identify the astrocytic MAOB-GABA axis as a crucial molecular and cellular brake on CNS repair system following SCI and highlight translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.

neuroscience↗

bioRxiv2021

Gabra5LHA Mediate Astrocytic GABA-induced Obesity via Decreasing Energy Expenditure

The lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

neuroscience↗

bioRxiv2021

Intravital imaging of cerebral microinfarct reveals an astrocyte reaction led to glial scar

Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage indicating blood-brain barrier (BBB) dysfunction. At day 5, edema disappeared with recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct. Oral administration of a reversible monoamine oxidase B inhibitor significantly decreased the astrocyte reactivity and fibrous scar formation. Our result suggests that astrocyte reactivity may be a key target to alleviate the impact of microinfarction.

neuroscience↗

bioRxiv2021

Visualization of reactive astrocytes in living brain of Alzheimer's disease patient

An early appearance of reactive astrocytes is a hallmark of Alzheimers disease (AD)1,2, providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.

neuroscience↗

bioRxiv2021

Visualizing reactive astrogliosis extends survival in glioblastoma patients

Glioblastoma multiforme (GBM) is a devastating brain tumor with dismal prognosis of only 15-month survival regardless of surgical resection. Here, we report an advanced neuroimaging technique combining 11C-acetate PET and MRI (AcePET), visualizing the boundary beyond the MRI-defined tumor. Targeted biopsy of the regions with increased 11C-acetate uptake revealed the presence of reactive astrocytes with enhanced acetate-transporter MCT1, along with cancer stem cells. Reactive astrogliosis and MCT1-dependent 11C-acetate-uptake were recapitulated in U87MG-orthotopic models. Mechanistically, glycolytic tumor cells release excessive acetate causing reactive astrogliosis, leading to the release of aberrant astrocytic GABA and H2O2, which further down-regulate the neuronal glucose uptake through GLUT3. Clincally, AcePET-guided surgery allows complete tumor resection of infiltrating cancer stem cells and extends the overall survival of patients by 5.25 months compared to conventional MRI-guided surgery. We established a new concept of the metabolic interactions between GBM cells and neighboring neurons through reactive astrocytes and developed AcePET-guided surgery to fight against GBM.

cancer biology↗

bioRxiv2020

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson's disease

Background and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinsons disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD. Experimental ApproachWe designed and synthesized -aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates. Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the -aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates. Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD. Representative Schematic O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY What is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor. MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis. What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD. KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates. What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinsons disease. Reversible MAO-B inhibitors could be more effective for treatment of Parkinsons disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.

pharmacology and toxicology↗

bioRxiv2020

Engineered Heterochronic Parabiosis in 3D Microphysiological System for Identification of Muscle Rejuvenating Factors

Exposure of aged mice to a young systemic milieu revealed remarkable rejuvenation effects on aged tissues, including skeletal muscle. Although some candidate factors have been identified, the exact identity and the underlying mechanisms of putative rejuvenating factors remain elusive, mainly due to the complexity of in vivo parabiosis. Here, we present an in vitro muscle parabiosis system that integrates young- and old-muscle stem cell vascular niche on a three-dimensional microfluidic platform designed to recapitulate key features of native muscle stem cell microenvironment. This innovative system enables mechanistic studies of cellular dynamics and molecular interactions within the muscle stem cell niche, especially in response to conditional extrinsic stimuli of local and systemic factors. We demonstrate that vascular endothelial growth factor (VEGF) signaling from endothelial cells and myotubes synergistically contribute to the rejuvenation of the aged muscle stem cell function. Moreover, with the adjustable on-chip system, we can mimic both blood transfusion and parabiosis and detect the time-varying effects of anti-geronic and pro-geronic factors in a single organ or multi-organ systems. Our unique approach presents a complementary in vitro model to supplement in vivo parabiosis for identifying potential anti-geronic factors responsible for revitalizing aging organs.

cell biology↗

bioRxiv2018

Targeting the CaV - interaction yields a selective antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy

Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of , {beta} and 2{delta} subunits. The {beta}-subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming subunit of CaV. We targeted the high-affinity protein-protein interface of CaV{beta}s pocket within the CaV-subunit. Structure-based virtual screening of 50,000 small molecule library docked to the {beta}-subunit led to the identification of 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide (compound 45). This small molecule bound to CaV{beta} and inhibited its coupling with N-type voltage-gated calcium (CaV2.2) channels, leading to a reduction in CaV2.2 currents in rat dorsal root ganglion (DRG) sensory neurons, decreased pre-synaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory post-synaptic potentials (sEPSC), and inhibited release of the nociceptive neurotransmitter calcitonin gene related peptide (CGRP) from spinal cord. 45 was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (post-surgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. 45 did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. 45, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaV-{beta} function and ultimately be developed as a non-opioid therapeutic for chronic pain.

neuroscience↗