Clinical Focus


  • neurogenic orthostatic hypotension
  • supine hypertension
  • Syncope, Vasovagal
  • baroreflex failure
  • sweating disorder
  • autonomic testing
  • Clinical Neurophysiology

Academic Appointments


Administrative Appointments


  • Program Director, Autonomic Disorders Fellowship, Stanford (2022 - Present)

Professional Education


  • Board Certification: United Council for Neurologic Subspecialties, Autonomic Disorders (2018)
  • Fellowship: Beth Israel Deaconess Medical Center (2016) MA
  • Board Certification, United Council for Neurological Subspecialties, Autonomic Disorders (2018)
  • Board Certification: American Board of Psychiatry and Neurology, Clinical Neurophysiology (2017)
  • Board certification, ABPN, Neurology (2015)
  • Residency: Medical University of South Carolina (2015) SC
  • Medical Education: Seoul National University (2002)

Clinical Trials


  • Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure Not Recruiting

    A Phase 3, 22-week, Multi-center, Randomized Withdrawal Study of ampreloxetine in Treating Symptomatic Neurogenic Orthostatic Hypotension in Subjects with Primary Autonomic Failure

    Stanford is currently not accepting patients for this trial.

    View full details

All Publications


  • Differential Findings on Anorectal Manometry in Patients with Parkinson's Disease and Defecatory Dysfunction. Movement disorders clinical practice Zhou, W., Triadafilopoulos, G., Gurland, B., Halawi, H., Becker, L., Garcia, P., Nguyen, L., Miglis, M., Muppidi, S., Sinn, D. I., Jaradeh, S., Neshatian, L. 2023; 10 (7): 1074-1081

    Abstract

    Gastrointestinal dysfunction, particularly constipation, is among the most common non-motor manifestations in Parkinson's Disease (PD). We aimed to identify high-resolution anorectal manometry (HR-ARM) abnormalities in patients with PD using the London Classification.We conducted a retrospective review of all PD patients at our institution who underwent HR-ARM and balloon expulsion test (BET) for evaluation of constipation between 2015 and 2021. Using age and sex-specific normal values, HR-ARM recordings were re-analyzed and abnormalities were reported using the London Classification. A combination of Wilcoxon rank sum and Fisher's exact test were used.36 patients (19 women) with median age 71 (interquartile range [IQR]: 69-74) years, were included. Using the London Classification, 7 (19%) patients had anal hypotension, 17 (47%) had anal hypocontractility, and 3 women had combined hypotension and hypocontractility. Anal hypocontractility was significantly more common in women compared to men. Abnormal BET and dyssynergia were noted in 22 (61%) patients, while abnormal BET and poor propulsion were only seen in 2 (5%). Men had significantly more paradoxical anal contraction and higher residual anal pressures during simulated defecation, resulting in more negative recto-anal pressure gradients. Rectal hyposensitivity was seen in nearly one third of PD patients and comparable among men and women.Our data affirms the high prevalence of anorectal disorders in PD. Using the London Classification, abnormal expulsion and dyssynergia and anal hypocontractility were the most common findings in PD. Whether the high prevalence of anal hypocontractility in females is directly related to PD or other confounding factors will require further research.

    View details for DOI 10.1002/mdc3.13755

    View details for PubMedID 37476327

    View details for PubMedCentralID PMC10354598

  • Differential Findings on Anorectal Manometry in Patients with Parkinson's Disease and Defecatory Dysfunction MOVEMENT DISORDERS CLINICAL PRACTICE Zhou, W., Triadafilopoulos, G., Gurland, B., Halawi, H., Becker, L., Garcia, P., Nguyen, L., Miglis, M., Muppidi, S., Sinn, D., Jaradeh, S., Neshatian, L. 2023

    View details for DOI 10.1002/mdc3.13755

    View details for Web of Science ID 000982806800001

  • Nonvestibular Dizziness. Otolaryngologic clinics of North America Jiam, N. T., Murphy, O. C., Gold, D. R., Isanhart, E., Sinn, D., Steenerson, K. K., Sharon, J. D. 2021; 54 (5): 999-1013

    Abstract

    Dizziness is a common chief complaint with an extensive differential diagnosis that ranges from peripheral, central, to nonvestibular conditions. An understanding of nonvestibular conditions will aid accurate diagnosis and initiation of appropriate management. Thus, the objective of this article is to present an overview of nonvestibular etiologies that may plague a dizzy patient and the recommended treatment options.

    View details for DOI 10.1016/j.otc.2021.05.017

    View details for PubMedID 34538360

  • Orthostatic intolerance with Klippel-Trenaunay syndrome. Clinical autonomic research : official journal of the Clinical Autonomic Research Society Sinn, D. I., Shaik, R., Miglis, M. G., Muppidi, S., Jaradeh, S. 2021

    View details for DOI 10.1007/s10286-021-00791-9

    View details for PubMedID 33655381

  • Autonomic function test during the COVID-19 pandemic: the Stanford experience. Clinical autonomic research : official journal of the Clinical Autonomic Research Society Sinn, D. I., Muppidi, S. n., Miglis, M. G., Jaradeh, S. n. 2021

    View details for DOI 10.1007/s10286-020-00752-8

    View details for PubMedID 33387099

  • A case report of postural tachycardia syndrome after COVID-19. Clinical autonomic research : official journal of the Clinical Autonomic Research Society Miglis, M. G., Prieto, T., Shaik, R., Muppidi, S., Sinn, D., Jaradeh, S. 2020

    View details for DOI 10.1007/s10286-020-00727-9

    View details for PubMedID 32880754

  • Symptom Recognition Is Impaired in Patients With Orthostatic Hypotension. Hypertension (Dallas, Tex. : 1979) Freeman, R., Illigens, B. M., Lapusca, R., Campagnolo, M., Abuzinadah, A. R., Bonyhay, I., Sinn, D., Miglis, M., White, J., Gibbons, C. H. 2020: HYPERTENSIONAHA11913619

    Abstract

    Failure to recognize symptoms of orthostatic hypotension (OH) may result in falls, syncope, and injuries. The relationship between orthostatic changes in blood pressure and symptom occurrence and severity is not known. The goal of the present study was to define the relationship between the occurrence and severity of the symptoms of orthostatic hypotension (OH) and (1) the upright systolic blood pressure (SBP) and (2) the fall in SBP after tilting in patients with OH. We prospectively studied 89 patients with OH. Reported BP values include the lowest BP in the first 3 minutes of tilt and the change in blood pressure during tilt. Subjects were queried about symptoms of orthostatic intolerance while supine and during the first 3 minutes of tilt testing using Question 1 of the Orthostatic Hypotension Questionnaire. Mean tilted SBP was 101.6±26.1 mm Hg and mean SBP fall 47.9±18.1 mm Hg. Mean symptom scores when upright were: light-headedness (2.3/10±2.7), dizziness (1.6/10±2.5), and impending blackout (0.8/10±1.9). The majority of patients were asymptomatic or mildly symptomatic and no discrete cutoff for symptoms was observed. The magnitude of the SBP fall (r=-0.07, P=NS) and the lowest upright SBP (r=0.08, P=NS) did not correlate with any reported symptom. These results suggest a poor relationship between the magnitude of the orthostatic BP fall, the upright orthostatic BP, and symptoms. Many patients are asymptomatic despite substantial SBP falls and low orthostatic blood pressures. These findings have implications for clinical care of patients with OH and clinical trials to treat patients with OH.

    View details for DOI 10.1161/HYPERTENSIONAHA.119.13619

    View details for PubMedID 32223377

  • Quantitative sudomotor abnormalities in clinically isolated rapid eye movement sleep behavior disorder. Autonomic neuroscience : basic & clinical Zitser, J., Muppidi, S., Sinn, D. I., Jaradeh, S., Miglis, M. G. 2020; 224: 102645

    Abstract

    BACKGROUND: Post-ganglionic sudomotor abnormalities are common in Parkinson's disease (PD), however data in clinically isolated REM sleep behavior disorder (iRBD) are limited.OBJECTIVE: To determine the prevalence of sudomotor abnormalities in a cohort of patients with iRBD.METHODS: We performed a retrospective review of patients seen in our autonomic clinic who underwent testing with the quantitative sudomotor axon reflex test (QSART). We identified three groups for comparison: 1.) iRBD, 2.) PD with RBD (PDwRBD) 3.) PD without RBD (PDwoRBD).RESULTS: PDwRBD (n=27) patients demonstrated the greatest sudomotor abnormalities (sudomotor CASS 1.44±1.24), followed by PDwoRBD (n=23, 0.57±0.5) and iRBD (n=20, 0.55±0.94) (p=0.015). Twenty percent of patients with iRBD had an abnormal result, compared to 67% PDwRBD and 35% PDwoRBD.DISCUSSION: Sudomotor abnormalities are common in patients with iRBD, supporting the concept that peripheral autonomic impairment occurs early in the course of disease.

    View details for DOI 10.1016/j.autneu.2020.102645

    View details for PubMedID 32062418

  • The Relationship Between Changes in Orthostatic Blood Pressure and Symptoms in Patients with Orthostatic Hypotension Freeman, R., Gibbons, C., Lapusca, R., Illigens, B., Campagnolo, M., Abuzinadah, A., Sinn, D. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Orthostatic Hypotension JACC State-of-the-Art Review JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Freeman, R., Abuzinadah, A. R., Gibbons, C., Jones, P., Miglis, M. G., Sinn, D. 2018; 72 (11): 1294–1309

    Abstract

    Neurogenic orthostatic hypotension is a highly prevalent and disabling feature of autonomic failure due to both peripheral and central neurodegenerative diseases. Community-based epidemiological studies have demonstrated a high morbidity and mortality associated with neurogenic orthostatic hypotension. It is due to impairment of baroreflex-mediated vasoconstriction of the skeletal muscle and splanchnic circulation and is caused by damage or dysfunction at central and/or peripheral sites in the baroreflex efferent pathway. Nonpharmacological and pharmacological interventions may be implemented to ameliorate the symptoms of orthostatic intolerance and improve quality of life. Many patients will be adequately treated by education, counseling, removal of hypotensive medications, and other nonpharmacological interventions, whereas more severely afflicted patients require pharmacological interventions. The first stage of pharmacological treatment involves repletion of central blood volume. If unsuccessful, this should be followed by treatment with sympathomimetic agents.

    View details for PubMedID 30190008

  • Rate of Stroke Mimics over Telestroke. Journal of stroke Sinn, D. I., Kasab, S. A., Banerjee, C. n., Ozark, S. n. 2017

    View details for PubMedID 28877562

  • Pathophysiology and Treatment of Orthostatic Hypotension in Parkinsonian Disorders. Current treatment options in neurology Sinn, D. I., Gibbons, C. H. 2016; 18 (6): 28

    Abstract

    Orthostatic hypotension (OH) is defined as a sustained pathological reduction in blood pressure within 3 min after orthostatic stress such as tilt-table testing or active standing. Non-neurogenic OH is caused by either decreased cardiac output or impaired vasoconstriction without a primary autonomic disorder whereas neurogenic OH results from inadequate release of norepinephrine in the vasomotor sympathetic system. Once non-neurogenic causes of OH such as medications and cardiac problems are ruled out, neurogenic OH can be considered. Neurogenic OH can accompany parkinsonian diseases in different stages and is associated with increased risk of morbidity and mortality. The pathophysiology of neurogenic OH in parkinsonian diseases includes sympathetic neurocirculatory failure and impaired cardiovagal activity. The inadequate release of peripheral norepinephrine upon orthostatic stress is a final pathologic pathway for neurogenic OH and is important for many therapeutic interventions. With mild or early autonomic failure, OH that occurs beyond 3 min of standing (defined as delayed OH) can result in orthostatic intolerance. Supine hypertension and postprandial hypotension are frequent comorbidities and may exacerbate orthostatic hypotension. The non-pharmacologic therapies should be tried initially, followed by pharmacologic treatments. Common medications used in the treatment of OH include fludrocortisone, midodrine, pyridostigmine, and droxidopa. Only midodrine and droxidopa have received FDA approval for the treatment of orthostatic hypotension.

    View details for DOI 10.1007/s11940-016-0410-9

    View details for PubMedID 27138287

  • Blood pressure oscillations in baroreflex failure. Clinical autonomic research : official journal of the Clinical Autonomic Research Society Abuzinadah, A. R., Sinn, D. I., Freeman, R. n., Gibbons, C. H. 2016

    Abstract

    A 67-year-old man presented with labile hypertension and orthostatic hypotension after radical neck dissection and radiotherapy for squamus cell carcinoma. Baroreflex failure is clearly evident on autonomic testing.

    View details for DOI 10.1007/s10286-016-0374-6

    View details for PubMedID 27541037

  • Simultaneous Optic Neuropathy and Osmotic Demyelinating Syndrome in Hyperemesis Gravidarum AMERICAN JOURNAL OF THE MEDICAL SCIENCES Sinn, D. I., Bachman, D., Feng, W. 2014; 347 (1): 88-90

    View details for DOI 10.1097/MAJ.0000000000000207

    View details for Web of Science ID 000329306400016

    View details for PubMedID 24366224

  • Ischemic Neuropathy Associated with Livedoid Vasculitis JOURNAL OF CLINICAL NEUROLOGY Kim, J., Park, S., Sinn, D. I., Kim, S., Hong, Y., Park, K. S., Sung, J., Lee, K. 2011; 7 (4): 233-236

    Abstract

    Livedoid vasculitis is a chronic dermatological problem with an unclear etiology. Clinical findings are petechiae with painful ulcers in both lower extremities, which heal to become hyperpigmented and porcelain-white satellite lesions. There are only a few reported cases of livedoid vasculitis presenting in combination with peripheral neuropathy.We report the first case of a Korean patient presenting with mononeuritis multiplex combined with livedoid vasculitis, which was confirmed by electrophysiological and pathological studies.Our report supports the possible vaso-occlusive etiology of livedoid vasculitis in multifocal ischemic neuropathy.

    View details for DOI 10.3988/jcn.2011.7.4.233

    View details for Web of Science ID 000298781200010

    View details for PubMedID 22259622

    View details for PubMedCentralID PMC3259500

  • Circulating endothelial progenitor cells as a new marker of endothelial dysfunction or repair in acute stroke STROKE Chu, K., Jung, K., Lee, S., Park, H., Sinn, D., Kim, J., Kim, D., Kim, J., Kim, S., Song, E., Kim, M., Lee, S. K., Roh, J. 2008; 39 (5): 1441-1447

    Abstract

    Understanding on distinct subsets of endothelial progenitor cells may provide insights of endothelial dysfunction or repair in the acute ischemic event. Recent in vitro data have reported the colony-forming unit (CFU) and outgrowth cell population as a subset of endothelial progenitor cells. In this study, we undertook to validate the significance of CFU number and outgrowth cell yield in acute stroke.Mononuclear cells were isolated from the peripheral blood of 75 patients with acute stroke, 45 patients with chronic stroke, and 40 age-matched healthy volunteers. CFU numbers were counted after culturing them for 7 days, and outgrowth cell appearance was measured during the 2 months of culture. Endothelial progenitor cell function was also evaluated by matrigel plate assays. Independent parameters predicting CFU number and outgrowth cell yield were assessed using logistic regression analysis.The CFU numbers and tube formation abilities in matrigel assays were significantly reduced in patients with acute stroke compared with patients with chronic stroke or healthy control subjects. Moreover, patients with large artery atherosclerosis had much lower CFU numbers and functional activities than ones with cardioembolism. Outgrowth cells were isolated from 10% of healthy control subjects and 22% of patients with chronic stroke during the cultures, but from 71% of patients with stroke. Multivariate analysis identified glycosylated hemoglobin and National Institutes of Health Stroke Scale on admission as significant independent predictors of a low CFU number and a high isolation frequency of outgrowth cells, respectively.CFU number may thus represent an accumulated endothelial progenitor cell dysfunctional status, whereas outgrowth cell appearance may reflect the resilience of the systemic circulation to acute ischemic stress.

    View details for DOI 10.1161/STROKEAHA.107.499236

    View details for Web of Science ID 000255393100009

    View details for PubMedID 18356550

  • Identification of neuronal outgrowth cells from peripheral blood of stroke patients ANNALS OF NEUROLOGY Jung, K., Chu, K., Lee, S., Song, E., Sinn, D., Kim, J., Kim, S., Kim, J., Kang, K., Park, H., Lee, S., Kim, M., Lee, S. K., Roh, J. 2008; 63 (3): 312-322

    Abstract

    Recent studies have identified a subset of outgrowth cell population with endothelial phenotype in long-term cultures of peripheral blood mononuclear cells. The concept that peripheral blood-derived cells participate in neuronal regeneration remains highly controversial, and no specific cell type has been identified. In this study, we undertook to characterize outgrowth cells in the peripheral blood culture from stroke patients.Mononuclear cells were isolated from the peripheral blood of 30 acute stroke patients, 20 risk factor-only subjects, and 20 healthy volunteers. The isolation frequency of outgrowth cells was measured during the 2 months of culture. The outgrowth cells were characterized by in vitro cultures and in vivo model of transplantation into the ischemic rat brain.Outgrowth cells could be more efficiently isolated from stroke patients (80%) than risk factor-only (30%) and healthy groups (10%). Outgrowth cells were more detected in the patients with greater National Institute of Health Stroke Scale scores (p = 0.023). They exhibited heterogenous populations with different morphologies, for example, cobblestone, palisading, or branching features. Two different types of outgrowth cells were identified: endothelial; neuronal, according to their morphological characteristics; and protein or gene expression profiles. The transplanted neuronal outgrowth cells survived in the ischemic rat brains over 6 months after transplantation. Targeted migration of the transplanted cells was seen in the ischemic brains with phenotypes of neuronal phenotypes.The feasibility of extracting and culturing neuronal outgrowth cells in large numbers suggests that such autologous cells will be useful for applications ranging from basic research to cell-based therapy.

    View details for DOI 10.1002/ana.21303

    View details for Web of Science ID 000254642500008

    View details for PubMedID 18257040

  • Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model BRAIN RESEARCH Kim, J., Lee, S., Chu, K., Jung, K., Song, E., Kim, S., Sinn, D., Kim, J., Park, D., Kang, K., Hong, N. H., Park, H., Won, C., Kim, K., Kim, M., Lee, S. K., Roh, J. 2007; 1183: 43-50

    Abstract

    Adipose-derived stem cells (ASCs) are readily accessible multipotent mesenchymal stem cells and are known to secrete multiple growth factors, and thereby to have cytoprotective effects in various injury models. In the present study, the authors investigated the neuroprotective effect of ASCs in an intracerebral hemorrhage (ICH) model. ICH was induced via the stereotaxic infusion of collagenase, and human ASCs (three million cells per animal) isolated from human fresh fat tissue, were intravenously administered at 24 h post-ICH induction. Acute brain inflammation markers, namely, cell numbers positively stained for terminal transferase dUTP nick end labeling (TUNEL), myeloperoxidase (MPO), or OX-42, and brain water content were checked at 3 days post-ICH. In addition, the authors quantified brain degeneration by measuring hemispheric atrophy and perihematomal glial thickness at 6 weeks post-ICH, and determined modified limb placing behavioral scores weekly over 5 weeks post-ICH. The results showed that brain water content, TUNEL+, and MPO+ cell numbers were significantly reduced in the ASC-transplanted rats. ASC transplantation attenuated neurological deficits from 4 to 5 weeks post-ICH, and reduced both the brain atrophy and the glial proliferation at 6 weeks. Transplanted ASCs were found to densely populate perihematomal areas at 6 weeks, and to express endothelial markers (von Willebrand factor and endothelial barrier antigen), but not neuronal or glial markers. In summary, ASCs transplantation in the ICH model reduced both acute cerebral inflammation and chronic brain degeneration, and promoted long-term functional recovery.

    View details for DOI 10.1016/j.brainres.2007.09.005

    View details for Web of Science ID 000251871600005

    View details for PubMedID 17920570

  • Neurotoxic syndrome developed after taking sertraline and risperidone JOURNAL OF CLINICAL NEUROLOGY Kim, J., Lee, S., Song, E., Jung, K., Sinn, D., Chung, H., Chu, K., Kim, M. 2007; 3 (3): 165-167

    Abstract

    Neuroleptic malignant syndrome and serotonin syndrome share many common clinical features, and the term "Neurotoxic syndrome" can be used when a clear distinction cannot be made between the two. Here we present a case of 19-year-old man who experienced serotonin syndrome caused by sertraline intake, and consecutive neuroleptic malignant syndrome by risperidone. This case suggests that these two syndromes can be concomitantly induced in some patients who are susceptible to these drugs. Clinicians may have to pay close attention to this problem when prescribing drugs to patients who previously showed sensitivity to CNS-acting drugs.

    View details for Web of Science ID 000254380000010

    View details for PubMedID 19513287

  • Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral Hemorrhage JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Jung, K., Chu, K., Lee, S., Kim, S., Song, E., Kim, E., Park, D., Sinn, D., Kim, J., Kim, M., Roh, J. 2007; 322 (3): 1051-1058

    Abstract

    Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.

    View details for DOI 10.1124/jpet.107.120097

    View details for Web of Science ID 000248887400018

    View details for PubMedID 17538008

  • Status epilepticus associated with sertindole EUROPEAN JOURNAL OF NEUROLOGY Sinn, D., Chu, K., Jung, K., Park, K., Nam, H., Lee, S. K. 2007; 14 (8): E12-E13
  • Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation NEUROBIOLOGY OF DISEASE Sinn, D., Kim, S., Chu, K., Jung, K., Lee, S., Song, E., Kim, J., Park, D., Lee, S. K., Kim, M., Roh, J. 2007; 26 (2): 464-472

    Abstract

    The modification of histone N-terminal tails by acetylation or deacetylation can alter the interaction between histones and DNA, and thus regulate gene expression. Recent experiments have demonstrated that valproic acid (VPA), a well-known anti-epileptic drug, can directly inhibit histone deacetylase (HDAC) activity and cause the hyperacetylation of histones. Moreover, VPA has been shown to mediate neuronal protection by activating signal transduction pathways and by inhibiting proapoptotic factors. In this study, we attempted to determine whether VPA alleviates cerebral inflammation and perihematomal cell death after intracerebral hemorrhage (ICH). Adult male rats received intraperitoneal injections of 300 mg/kg VPA or PBS twice a day after ICH induction. VPA treatment inhibited hematoma expansion, perihematomal cell death, caspase activities, and inflammatory cell infiltration. In addition, VPA treatment had the following expressional effects; it activated the translations of acetylated histone H3, pERK, pAKT, pCREB, and HSP70; up-regulated bcl-2 and bcl-xl but down-regulated bax; and down-regulated the mRNAs of Fas-L, IL-6, MMP-9, MIP-1, MCP-1, and tPA. VPA-treated rats also showed better functional recovery from 1 day to 4 weeks after ICH. Here we show that VPA induces neuroprotection in a murine ICH model and that its neuroprotective effects are mediated by transcriptional activation following HDAC inhibition.

    View details for DOI 10.1016/j.nbd.2007.02.006

    View details for Web of Science ID 000245994000016

    View details for PubMedID 17398106

  • Proteasomal inhibition in intracerebral hemorrhage: Neuroprotective and anti-inflammatory effects of bortezomib NEUROSCIENCE RESEARCH Sinn, D., Lee, S., Chu, K., Jung, K., Kim, E., Kim, J., Park, D., Song, E., Kim, B., Yoon, S., Kim, M., Roh, J. 2007; 58 (1): 12-18

    Abstract

    Inflammation is an important pathophysiologic mechanism of injury induced by intracerebral hemorrhage (ICH). The ubiquitin-proteasome system (UPS) regulates the inflammatory responses via the up-regulation of several pro-inflammatory molecules. In this study, we determined that a potent proteasome inhibitor, bortezomib, exerted therapeutic effects in experimental model of ICH. Either bortezomib (0.05, 0.2, 0.5, 1mg/kg) or vehicle was intravenously administered 2h after ICH induction. The high doses of bortezomib caused high mortality rates. Bortezomib at 0.2 mg/kg reduced the early hematoma growth and alleviated hematoma volume and brain edema at 3 days after ICH, compared with the ICH-vehicle group. The numbers of myeloperoxidase(+) neutrophils, Ox42(+) microglia, and TUNEL(+) cells in the perihematomal regions were decreased by bortezomib. Bortezomib induced significant decrements of mRNA expression of TNF-alpha and IL-6. The production of iNOS and COX2 was also reduced significantly by bortezomib. We concluded that the early treatment with bortezomib induced a reduction in the early hematoma growth and mitigated the development of brain edema, coupled with a marked inhibitory effect on inflammation in ICH.

    View details for DOI 10.1016/j.neures.2007.01.006

    View details for Web of Science ID 000247013900003

    View details for PubMedID 17328981

  • Pharmacological induction of heat shock protein exerts neuroprotective effects in experimental intracerebral hemorrhage BRAIN RESEARCH Sinn, D., Chu, K., Lee, S., Song, E., Jung, K., Kim, E., Park, D., Kang, K., Kim, M., Roh, J. 2007; 1135 (1): 167-176

    Abstract

    Heat shock proteins (HSPs) are reported to reduce inflammation and apoptosis in a variety of brain insults. Geranylgeranylacetone (GGA), developed as an antiulcer in Japan, has been known to induce HSP70 and to exert cytoprotective effects. In this study, we investigated whether GGA, as a specific HSP inducer, exerts therapeutic effects in experimentally induced intracerebral hemorrhage (ICH). ICH was induced with male Sprague-Dawley rats via the collagenase infusion. GGA (800 mg/kg) was administered via oral tube according to various schedules of treatment. The treatment with GGA, beginning before the induction of ICH and continuing until day 3, showed the reduction of brain water content and the increased level of HSP70 protein, as compared to the treatment with vehicle, although GGA started after the induction of ICH or administered as a single dose before ICH failed to up-regulate HSP70 and to reduce brain edema. The rats treated with GGA exhibited better functional recovery than those treated with vehicle. In the pre- and post- treatment group, inflammatory cells and cell death in the perihematomal regions were found to have been decreased. The treatment of GGA inhibited the mRNA expression of MMP-9, uPA, IL-6 and MIP-1, with concomitant increment of eNOS and phosphorylated STAT3 and Akt after ICH. We demonstrated that GGA induced a reduction in the brain edema along with marked inhibitory effects on inflammation and cell death after ICH.

    View details for DOI 10.1016/j.brainres.2006.11.098

    View details for Web of Science ID 000244551900019

    View details for PubMedID 17208204

  • Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage NEUROSCIENCE LETTERS Sinn, D., Lee, S., Chu, K., Jung, K., Song, E., Kim, J., Park, D., Kim, M., Roh, J. 2007; 411 (3): 238-242

    Abstract

    Memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, inhibits hematoma expansion and celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduces perihematomal inflammation in intracerebral hemorrhage. We examined whether the combination treatment has additive effects in experimental intracerebral hemorrhage (ICH). ICH was induced using stereotaxic infusion of collagenase into brains of adult rats. After the induction of ICH, rats were treated with intraperitoneal injection of memantine (20 mg/kg), celecoxib (20 mg/kg) or both agents. Only vehicles were administrated in rats of the control group. Results showed that the combination treatment of memantine and celecoxib reduced both hematoma volume and brain edema. Combination treatment also induced the better functional recovery with further attenuation of cerebral inflammation and apoptosis compared to the control group. When compared to the single agent groups, the combination treatment showed better effects in neuroprotection and anti-inflammation. These results suggest the feasible combined application of memantine and celecoxib in ICH treatment.

    View details for DOI 10.1016/j.neulet.2006.10.050

    View details for Web of Science ID 000244078300015

    View details for PubMedID 17123715

  • Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury STROKE Jung, K., Chu, K., Ko, S., Lee, S., Sinn, D., Park, D., Kim, J., Song, E., Kim, M., Roh, J. 2006; 37 (11): 2744-2750

    Abstract

    The rate of nitric oxide (NO) generation from nitrite is linearly dependent on reductions in oxygen and pH levels. Recently, nitrite-derived NO has been reported to exert a profound protection against liver and heart ischemia-reperfusion injury. In this study, we hypothesized that nitrite would be reduced to NO in the ischemic brain and exert NO-dependent neuroprotective effects.Cerebral ischemia-reperfusion injury was induced by intraluminal thread occlusion of middle cerebral artery in the adult male rats. Solutions of sodium nitrite were infused intravenously at the time of reperfusion. Sodium nitrate and carboxy-PTIO (30 minutes before ischemic surgery), a direct NO scavenger, were infused for comparisons.Nitrite reduced infarction volume and enhanced local cerebral blood flow and functional recovery. The effects were observed at concentrations of 48 nmol and 480 nmol, but not at 4800 nmol nitrite and 480 nmol nitrate. The neuroprotective effects of nitrite were inhibited completely by the carboxy-PTIO. The 480 nmol nitrite attenuated dihydroethidium activity, 3-nitrotyrosine formation, and lipid peroxidation in the ischemic brain.Nitrite exerted profound neuroprotective effects with antioxidant properties in the ischemic brains. These results suggest that nitrite, as a biological storage reserve of NO, may be a novel therapeutic agent in the setting of acute stroke.

    View details for DOI 10.1161/01.STR.0000245116.40163.1c

    View details for Web of Science ID 000241798800027

    View details for PubMedID 17008610

  • Quantification of human neural stem cell engraftments in rat brains using ERV-3 real-time PCR JOURNAL OF NEUROSCIENCE METHODS Lee, S., Chu, K., Kim, E., Jung, K., Lee, K., Sinn, D., Kim, S. U., Kim, M., Roh, J. 2006; 157 (2): 225-229

    Abstract

    Few sensitive and reliable methods have been available for quantifying the number of transplanted human neural stem cells (hNSC) in the animal brain. To develop an accurate method for quantifying the number of hNSC incorporated in rat brain, we performed real-time PCR on hNSC-transplanted rat brains using a target sequence for ERV-3, which is an endogenous retrovirus present with a known copy number in all human cells, but not present in rodent cells. A standard curve was developed for known amount of different mixes of hNSC and rat fibroblasts, and test samples were prepared by manually incorporating variable, predefined numbers of hNSCs into rat brains. A cerebral rat hemisphere injected with 10(7) hNSC revealed 1.125% chimerism. Moreover, a linear correlation was found between hNSC numbers injected and their concentrations in the rat brain. In conclusion, the developed quantitative ERV-3 assay enables a simple, fast, and reproducible detection and quantitation of hNSC numbers in the rat brain.

    View details for DOI 10.1016/j.jneumeth.2006.04.019

    View details for Web of Science ID 000241753600005

    View details for PubMedID 16735065

  • Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus NEUROBIOLOGY OF DISEASE Jung, K., Chu, K., Lee, S., Kim, J., Sinn, D., Kim, J., Park, D., Lee, J., Kim, S. U., Kim, M., Kun Lee, S., Roh, J. 2006; 23 (2): 237-246

    Abstract

    Recent evidences suggest key roles of abnormal neurogenesis and astrogliosis in the pathogenesis of epilepsy. Alterations in the microenvironment of the stem cell, such as microglial activation and cyclooxygenase-2 induction may cause ectopic neurogenesis or astrogliosis. Here, we examined if inflammatory blockade with celecoxib, a selective cyclooxygenase-2 inhibitor, could modulate the altered microenvironment in the epileptic rat brain. Celecoxib attenuated the likelihood of developing spontaneous recurrent seizures after pilocarpine-induced prolonged seizure. During the latent period, celecoxib prevented neuronal death and microglia activation in the hilus and CA1 and inhibited the generation of ectopic granule cells in the hilus and new glia in CA1. The direct inhibition of precursor cells by celecoxib was further demonstrated in human neural stem cells culture. These findings raise the evidence of COX-2 induction to act importantly on epileptogenesis and suggest a potential therapeutic role for COX-2 inhibitors in chronic epilepsy.

    View details for DOI 10.1016/j.nbd.2006.02.016

    View details for Web of Science ID 000239611700001

    View details for PubMedID 16806953

  • Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia BRAIN RESEARCH Chu, K., Lee, S., Koo, J., Jung, K., Kim, E., Sinn, D., Kim, J., Ko, S., Kim, S., Song, E., Kim, M., Roh, J. 2006; 1093: 208-218

    Abstract

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, not only improves insulin resistance in patients with type II diabetes but also exerts a broad spectrum protective effects in variable animal models of neurologic or cardiovascular diseases. We studied the effect of rosiglitazone on angiogenesis and neurological recovery after focal cerebral ischemia. Rosiglitazone (3 mg/kg or 0.3 mg/kg, p.o.) was administered for 7 days prior to and 3 days after the induction of focal ischemia (total 10 days) in adult rats. The rosiglitazone-treated group showed the enhanced neurologic improvement, the reduced infarction volume compared to the ischemia-vehicle group with dose dependency, and the reduced hemispheric atrophy. Rosiglitazone treatment reduced TUNEL(+)/activated caspase-3(+) cells, MPO(+)/Ox-42(+) inflammatory cell infiltrations, caspase-3 activity, and Bax(+) cells, as compared to the ischemia-vehicle group. The vascular surface area, the vascular branch points, the vascular length, and the number of BrdU(+) endothelial cells were significantly increased in the rosiglitazone group compared with the ischemia-vehicle group. Rosiglitazone increased eNOS expression around the ischemic margin with downregulation of FasL. Here, we show that rosiglitazone treatment enhances angiogenesis and functional recovery with dose-dependent induction of ischemic tolerance.

    View details for DOI 10.1016/j.brainres.2006.03.014

    View details for Web of Science ID 000239068100022

    View details for PubMedID 16696956

  • Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LEE, S. T., Chu, K., Jung, K. H., Kim, J., Kim, E. H., Kim, S. J., Sinn, D. I., Ko, S. Y., Kim, M., Roh, J. K. 2006; 26 (4): 536-544

    Abstract

    Glutamate is accumulated in abundance during the early period of experimental hematoma, and the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate can result in an influx of calcium and neuronal death in cases of intracerebral hemorrhage (ICH). Memantine, which is known to be a moderate-affinity, uncompetitive, NMDA receptor antagonist, was investigated with regard to its ability to block the glutamate overstimulation and tissue plasminogen activator (tPA)/urokinase plasminogen activator (uPA)/matrix metalloproteinase (MMP)-9 modulation in experimental ICH. Intracerebral hemorrhage was induced via the infusion of collagenase into the left basal ganglia of adult rats. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered 30 min after the induction of ICH, and, at daily intervals afterwards, for either 3 or 14 days. Hemorrhage volume decreased by 47% in the memantine group, as compared with the ICH-only group. In the memantine group, the numbers of TUNEL+, myeloperoxidase (MPO)+, and OX42+ cells decreased in the periphery of the hematoma. Memantine resulted in an upregulation of bcl-2 expression and an inhibition of caspase-3 activation. Memantine also exerted a profound inhibitory effect on the upregulation of tPA/uPA mRNA, and finally decreased the MMP-9 level in the hemorrhagic brain. In modified limb-placing test, the memantine-treated rats exhibited lower scores initially, and recovered more quickly and thoroughly throughout the 35 days of the study. Here, we show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/uPA and MMP-9 level. Subsequently, memantine was found to reduce inflammatory infiltration and apoptosis, and was also determined to induce functional recovery after ICH.

    View details for DOI 10.1038/sj.jcbfm.9600213

    View details for Web of Science ID 000236340400009

    View details for PubMedID 16107786

  • Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage JOURNAL OF NEUROCHEMISTRY LEE, S. T., Chu, K., Sinn, D. I., Jung, K. H., Kim, E. H., Kim, S. J., Kim, J. M., Ko, S. Y., Kim, M., Roh, J. K. 2006; 96 (6): 1728-1739

    Abstract

    Erythropoietin (EPO), a pleiotropic cytokine involved in erythropoiesis, is tissue-protective in ischemic, traumatic, toxic and inflammatory injuries. In this study, we investigated the effect of EPO in experimental intracerebral hemorrhage (ICH). Two hours after inducing ICH via the stereotaxic infusion of collagenase, recombinant human EPO (500 or 5000 IU/kg, ICH + EPO group) or PBS (ICH + vehicle group) was administered intraperitoneally, then once daily afterwards for 1 or 3 days. ICH + EPO showed the better functional recovery in both rotarod and modified limb placing tests. The brain water content was decreased in ICH + EPO dose-dependently, as compared with ICH + vehicle. The effect of EPO on the brain water content was inhibited by N(omega)-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg). Mean hemorrhage volume was also decreased in ICH + EPO. EPO reduced the numbers of TUNEL +, myeloperoxidase + or OX-42 + cells in the perihematomal area. In addition, EPO reduced the mRNA level of TNF-alpha, Fas and Fas-L, as well as the activities of caspase-8, 9 and 3. EPO treatment showed up-regulations of endothelial nitric oxide synthase (eNOS) and p-eNOS, pAkt, pSTAT3 and pERK levels. These data suggests that EPO treatment in ICH induces better functional recovery with reducing perihematomal inflammation and apoptosis, coupled with activations of eNOS, STAT3 and ERK.

    View details for DOI 10.1111/j.1471-4159.2006.03697.x

    View details for Web of Science ID 000235842100022

    View details for PubMedID 16539688

  • Granulocyte colony-stimulating factor stimulates neurogenesis via vascular endothelial growth factor with STAT activation. Brain research Jung, K., Chu, K., Lee, S., Kim, S., Sinn, D., Kim, S. U., Kim, M., Roh, J. 2006; 1073-1074: 190-201

    Abstract

    The adult brain harbors multipotent stem cells, which reside in specialized niches that support self-renewal. Granulocyte colony-stimulating factor (G-CSF) induces bone marrow stem cells proliferation and mobilization from their niche, and activates endothelial cell proliferation, which might help to establish a vascular niche for neural stem cells (NSCs). Here, we show that G-CSF induced receptor-mediated proliferation and differentiation of neural precursors in human NSCs cultures and in adult rat brain in vivo. In human NSCs cultures, G-CSF activated STAT3 and 5, and increased VEGF and its receptor, VEGFR2 (Flk-1) expression, and VEGFR2 tyrosine kinase inhibitor blocked the neurogenesis stimulated by G-CSF. G-CSF also activated endothelial cell proliferation in adult rat brain in vivo. Our results indicate that G-CSF stimulates neurogenesis through reciprocal interaction with VEGF and STAT activation.

    View details for PubMedID 16423324

  • Combined treatment of vascular endothelial growth factor and human neural stem cells in experimental focal cerebral ischemia NEUROSCIENCE RESEARCH Chu, K., Park, K. I., LEE, S. T., Jung, K. H., Ko, S. Y., Kang, L., Sinn, D. I., Lee, Y. S., Kim, S. U., Kim, M., Roh, J. K. 2005; 53 (4): 384-390

    Abstract

    Recent studies have indicated the beneficial effects of vascular endothelial growth factor (VEGF), and transplanted neural stem cells (NSCs) in cerebral ischemia. We investigated the effects of the combined administration of NSCs and VEGF on focal cerebral ischemia in adult rats. Four groups (n = 12, respectively)--group 1 (ischemia-only), group 2 (ischemia + VEGF), group 3 (ischemia + NSCs) and group 4 (ischemia + NSCs + VEGF)--were compared. Human NSCs (HB1.F3), labeled with Lac Z+ or PKH26, were given intravenously 24h after surgery (5 x 10(6) cells). At 48 h after surgery, recombinant human VEGF (50 microg/kg) was infused intravenously (1 microg/(kg min)). Behavioral tests using the modified limb placing and rotarod tests were performed every week following ischemia. Immunohistochemistry for endothelial barrier antigen (EBA), VEGF and Nissl staining were performed at day 35 after ischemia. Group 4 showed better behavioral recovery at 7, 14 and 28 days than group 3 (p = 0.020, 0.005 and 0.043, respectively). These functional recoveries were correlated with enhanced EBA immunoreactivities at day 35 after ischemia, especially in the ipsilesional striatum. Group 4 showed lesser degree of brain atrophy in cortex and striatum, when compared with other groups. The distribution of VEGF was not co-localized with NSCs. Our results suggest that VEGF may act synergistically on NSC-transplanted, ischemic brain via a pro-angiogenic effect.

    View details for DOI 10.1016/j.neures.2005.08.010

    View details for Web of Science ID 000234017400005

    View details for PubMedID 16198014

  • Granulocyte colony-stimulating factor enhances anglogenesis after focal cerebral ischemia BRAIN RESEARCH LEE, S. T., Chu, K., Jung, K. H., Ko, S. Y., Kim, E. H., Sinn, D. I., Lee, Y. S., Lo, E. H., Kim, M., Roh, J. K. 2005; 1058 (1-2): 120-128

    Abstract

    Granulocyte colony-stimulating factor (G-CSF) is a neuroprotective agent and activates endothelial proliferation and bone marrow stem cell mobilization. We studied the effect of G-CSF on angiogenesis and neurological recovery after focal cerebral ischemia. After the induction of transient focal ischemia in rats, G-CSF (50 micro/day, i.p.) or PBS was administered for 3 days. We evaluated the functional recovery, infarct volume, inflammatory infiltration, blood-brain barrier (BBB) disruption, hemispheric atrophy, protein expressions of endothelial nitric oxide synthase (eNOS) and angiopoietins, and the therapeutic time window of G-CSF administration. We then analyzed endothelial cell proliferation, the vascular surface area, the number of branch points, and the vascular length. G-CSF treatment improved behavioral recovery and reduced the infarct volume, the inflammatory infiltration, the BBB disruption, and the hemispheric atrophy. G-CSF injection, starting at 2 h, 1 day, or 4 days after ischemia, resulted in a better functional recovery and a greater reduction in hemispheric atrophy than injection starting at day 7. The vascular surface area, the vascular branch points, the vascular length, the number of BrdU(+) endothelial cells, and eNOS/angiopoietin-2 expression were significantly increased in the G-CSF group compared with the ischemia-only group. G-CSF injection starting at 1 day induced larger endothelial proliferation compared with injection starting at 7 days. In this study, we provide evidences that G-CSF enhances the angiogenesis and reduces the ischemic damage, which promotes the long-term functional recovery.

    View details for DOI 10.1016/j.brainres.2005.07.076

    View details for Web of Science ID 000232868700013

    View details for PubMedID 16150422