Jai Sung Noh

Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I.

We examined effects of two insulin-like growth factors, insulin and insulin-like growth factor-I (IGF-I), against apoptosis, excitotoxicity, and free radical neurotoxicity in cortical cell cultures. Like IGF-I, insulin attenuated serum deprivation-induced neuronal apoptosis in a dose-dependent manner at 10-100 ng/mL. The anti-apoptosis effect of insulin against serum deprivation disappeared by addition of a broad protein kinase inhibitor, staurosporine, but not by calphostin C, a selective protein kinase C inhibitor. Addition of PD98059, a mitogen-activated protein kinase kinase (MAPKK) inhibitor, blocked insulin-induced activation of extracellular signal-regulated protein kinases (ERK1/2) without altering the neuroprotective effect of insulin. Cortical neurons underwent activation of phosphatidylinositol (PI) 3-kinase as early as 1 min after exposure to insulin. Inclusion of wortmannin or LY294002, selective inhibitors of PI 3-K, reversed the insulin effect against apoptosis. In contrast to the anti-apoptosis effect, neither insulin nor IGF-I protected excitotoxic neuronal necrosis following continuous exposure to 15 microM N-methyl-D-aspartate or 40 microM kainate for 24 h. Surprisingly, concurrent inclusion of 50 ng/mL insulin or IGF-I aggravated free radical-induced neuronal necrosis over 24 h following continuous exposure to 10 microM Fe2+ or 100 microM buthionine sulfoximine. Wortmannin or LY294002 also reversed this potentiation effect of insulin. These results suggest that insulin-like growth factors act as anti-apoptosis factor and pro-oxidant depending upon the activation of PI 3-kinase.

Neurotoxic and Neuroprotective Actions of Catecholamines in Cortical Neurons

We examined the possibility that catecholamines (CA) could act as endogenous modulators of neuronal death. Exposure to high doses (>100 microM) of dopamine (DA) caused widespread neuronal death within 24 h in mouse cortical cell cultures and was accompanied by cell body shrinkage, aggregation and condensation of nuclear chromatin, and prominent internucleosomal DNA fragmentation. Epinephrine, but not norepinephrine (NE), was slightly toxic to neurons at doses higher than 1 mM. DA-induced death was attenuated by the addition of three different anti-apoptosis agents, 1 microgram/ml cycloheximide, 25 mM K(+), or 100 ng/ml brain-derived neurotrophic factor (BDNF). While treatment with 100 microM N-acetyl-l-cysteine attenuated DA neurotoxicity, neither the glutamate antagonists (10 microM MK-801 plus 50 microM CNQX) nor several antioxidants [trolox, 100 microM; Mn (III) tetrakis (4-benzoic acid) porphyrin chloride, 100 microM; Mn (III) tetrakis (1-methyl-4-pyridyl) prophyrin pentachloride, 100 microM; N-tert-butyl-alpha-phenylnitrone, 3 mM] prevented the CA-induced apoptosis. Interestingly, all CA at 1-30 microM attenuated free radical-mediated neuronal necrosis following exposure to 30 microM Fe(2+) or 200 microM H(2)O(2), which was insensitive to DA or NE antagonists. Like trolox, CA reduced levels of the stable free radical 1,1-diphenyl-2-picrylhydrazyl under cell-free conditions, raising the possibility that CA as an antioxidant protects neurons. We also found that the neuroprotective effect of CA prolonged the protective effects of BDNF against serum deprivation. The present findings suggest that CA induces apoptosis at high doses but prevents free radical-mediated neurotoxicity as an anti-oxidant without being coupled to the receptors.

Concurrent administration of Neu2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis.

The Fas pathway and oxidative stress mediate neuronal death in stroke and may contribute to neurodegenerative disease. We tested the hypothesis that these two factors synergistically produce spinal motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Levels of reactive oxygen species were increased in motor neurons from ALS mice compared with wild-type mice at age 10 weeks, before symptom onset. The proapoptotic proteins Fas, Fas-associated death domain, caspase 8, and caspase 3 were also elevated. Oral administration of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000), a potent antioxidant, blocked the increase in reactive oxygen species but only slightly reduced activation of proapoptotic proteins. Administration of lithium carbonate (Li+), a mood stabilizer that prevents apoptosis, blocked the apoptosis machinery without preventing oxidative stress. Neu2000 or Li+ alone significantly enhanced survival time and motor function and together had an additive effect. These findings provide evidence that jointly targeting oxidative stress and Fas-mediated apoptosis can prevent neuronal loss and motor dysfunction in ALS.

Attenuation of Oxidative Neuronal Necrosis by a Dopamine D1 Agonist in Mouse Cortical Cell Cultures

Events which lead to an increase in intracellular free radicals induce necrotic cell death of cultured cortical neurons. In the present study, we report that treatment with 1 microM (+/-)-SKF-38393 hydrochloride, a selective D1 agonist, as well as 100 microM trolox, a lipophilic vitamin E analogue, significantly prevented oxidative-related necrotic cell death following exposure to 10 microM Fe2+ or 1 mM buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase. The neuroprotective effect of (+/-)-SKF-38393 hydrochloride was partially reversed by addition of (+/-)-SKF-83566 hydrochloride, a selective D1 antagonist. Quinelorane dihydrochloride, a selective D2 agonist, did not influence free radical neurotoxicity. Interestingly, inclusion of (+/-)-SKF-38393 hydrochloride or quinelorane dihydrochloride did not attenuate apoptotic cell death of cortical neurons deprived of serum. The present study provides evidence that (+/-)-SKF-38393 hydrochloride attenuates oxidative neuronal necrosis, which has unique therapeutic potential for the treatment of various neurodegenerative diseases linked to oxidative stress.

The functional and neuroprotective actions of Neu2000, a dual-acting pharmacological agent, in the treatment of acute spinal cord injury.

The goal of the present study was to examine the neuroprotective and functional significance of targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress using a dual-acting compound, Neu2000, in rat model of moderate spinal cord injury (SCI). An initial set of experiments was conducted in uninjured rats to study the pharmacokinetic profile of Neu2000 following intraperitoneal and intravenous administration. A second experiment measured free radical production in mitochondria isolated from sham or injured spinal cords of animals receiving vehicle or Neu2000 treatment. A third set of animals was divided into three treatment groups consisting of vehicle treatment, a single dose of Neu2000 (50 mg/kg) administered at 10 min following injury, or a repeated treatment paradigm consisting of a single bolus of Neu2000 at 10 min following injury (50 mg/kg) plus a maintenance dose (25 mg/kg) administered every 24 h for an additional 6 days. Animals were tested once a week for a period of 6 weeks for evidence of locomotor recovery in an open field and kinematic analysis of fine motor control using the DigiGait Image Analysis System. At the end of the testing period, spinal cord reconstruction was performed to obtain nonbiased stereological measures of tissue sparing. The results of this study demonstrate that Neu2000 treatment significantly reduced the production of mitochondrial free radicals and improved locomotor outcomes that were associated with a significant increase in the volume of spared spinal cord tissue.

A distinct death mechanism is induced by 1-methyl-4-phenylpyridinium or by 6-hydroxydopamine in cultured rat cortical neurons: Degradation and dephosphorylation of tau

We examined whether the well-known neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP(+)) recruit distinct cell death mechanisms using primary cultured neurons derived from day 16 embryonic rat cortices. Electron microscopy revealed that cell death induced by both 6-OHDA and MPP(+) was typified by a condensation of chromatin while prominent mitochondrial swelling was observed only in those cells treated with MPP(+). Co-treatment of cells with a pan-caspase inhibitor, Z-VAD-fmk, attenuated 6-OHDA-induced chromatin condensation and neuronal death. Co-treatment with such antioxidants as N-acetylcysteine or Mn-TBAP also suppressed 6-OHDA-induced cell death. None of these treatments attenuated MPP(+)-induced cell death although caspase inhibition abolished MPP(+)-induced chromatin condensation. Interestingly, in these paradigms of cell death, the N-terminus of tau was specifically cleaved and the levels of phosphorylated tau were markedly decreased following 6-OHDA treatment. By contrast, the C-terminus of tau was cleaved in MPP(+)-induced cell death while the levels of phosphorylated tau remained largely unaltered. Taken together, our results indicate that distinct cellular mechanisms appear to underlie neurotoxin-induced cortical neuronal cell death.

Effects of a Multidomain Lifestyle Modification on Cognitive Function in Older Adults: An Eighteen-Month Community-Based Cluster Randomized Controlled Trial

Background: A healthy lifestyle may protect against cognitive decline. We examined outcomes in elderly individuals after 18 months of a five-group intervention program consisting of various modalities to prevent cognitive decline. Methods: We conducted a cluster randomized controlled trial assessing 460 community-dwelling individuals aged 60 years and older in a geriatric community mental health center in Suwon, Republic of Korea, between 2008 and 2010. We developed an intervention program based on the principles of contingency management, which could be delivered by ordinary primary health workers. Group A (n = 81) received standard care services. Group B (n = 80) received bimonthly (once every 2 months) telephonic care management. Group C (n = 111) received monthly telephonic care management and educational materials similar to those in group B. Group D (n = 93) received bimonthly health worker-initiated visits and counseling. Group E (n = 94) received bimonthly health worker-initiated visits, counseling, and rewards for adherence to the program. Results: The primary outcome was the change in Mini-Mental State Examination (MMSE) scores from baseline to the final follow-up visit at 18 months. Group E showed superior cognitive function to group A (adjusted coefficient β = 0.99, p = 0.044), with participation in cognitive activities being the most important determining factor among several health behaviors (adjusted coefficient β = 1.04, p < 0.01). Conclusions: Engaging in cognitive activities, in combination with positive health behaviors, may be most beneficial in preserving cognitive abilities in community-dwelling older adults.

5-Hydroxytryptamine attenuates free radical injury in primary mouse cortical cultures.

The effects of 5-hydroxytryptamine (5-HT) on several types of neuronal injury in mouse cortical cell cultures were tested. Co-treatment with 5-HT prevented free radical-mediated neuronal necrosis induced by FeCl2 or buthionine sulfoximine (BSO) in a dose-dependent manner. Subtype antagonists did not reverse the protective effect and 5-HT showed direct free radical scavenging activity evidenced by its ability to reduce the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) in a cell-free system. Excitotoxic necrosis induced by NMDA or apoptosis induced by staurosporine was not sensitive to 5-HT treatment. These features raise the possibility that the endogenous neurotransmitter 5-HT may work as an innate antioxidant defense mechanism in the CNS.

Effect of Psychotropic Drugs on Development of Diabetes Mellitus in Patients With Alzheimer's Disease

Abstract We aimed to examine risk of diabetes mellitus (DM) among older adults with Alzheimers disease receiving 3 types of psychotropic drugs, that is, antipsychotics, antidepressants, and sedative anxiolytics. We retrospectively analyzed data from a hospital-based Clinical Research Center for Dementia of South Korea (CREDOS) study conducted between January 1, 2008 and December 31, 2012. Participants (n = 3042) with Alzheimers disease were aged 65 or older and had no preexisting history of DM. Development of DM was identified using claims for initiating at least 1 prescription of antidiabetic medications or a diagnosis of DM during the follow-up period. Cox proportional hazards regression was used to demonstrate the Hazard ratio of DM in use of each psychotropic drug. Among the 3042 participants, 426 patients (14.0%) developed DM, representing an incidence rate of 5.2/100 person-years during an average 2.9 years of follow-up period. Among the 3 types of psychotropic drugs, antipsychotic users had a significantly higher risk of DM (hazard ratio = 1.74, 95% confidence interval = 1.10, 2.76) than nonusers, after adjusting covariates. Antidepressants and sedative anxiolytics did not achieve statistical significance. These results suggested that the diabetes risk was elevated in Alzheimer patients on antipsychotic treatment. Therefore, patients with Alzheimers disease receiving antipsychotic treatment should be carefully monitored for the development of DM.

Clinical Conversion or Reversion of Mild Cognitive Impairment in Community versus Hospital Based Studies: GDEMCIS (Gwangju Dementia and Mild Cognitive Impairment Study) and CREDOS (Clinical Research Center for Dementia of South Korea)

BACKGROUND In keeping with increasing interest in dementia, few recent studies suggest that clinical course of mild cognitive impairment vary across different studies with hospital-based subjects showing higher rates of conversion than community-based subjects. OBJECTIVE The main objective of the present study was to assess whether the clinical conversion or reversion rates differ according to recruitment source. METHODS The baseline study subjects comprised of patients who were diagnosed with mild cognitive impairment in community-based GDEMCIS or hospital-based CREDOS. The two studies had nearly the same protocol and were performed over a similar period. We used propensity score matching for baseline comparability. After that, Cox proportional hazards regression analyses were conducted to estimate the hazard ratios and 95% confidence intervals of clinical conversion or reversion. RESULTS Based on 89 GDEMCIS subjects, 1 : 4 propensity score matching was conducted and 356 CREDOS subjects were selected. After adjusting for covariates including baseline demographics, comorbidity, depression, disability, and neuropsychological result, Cox proportional hazard regression analysis for time to clinical conversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 2.13 (95% CI, 1.08-4.21), as compared to recruitment from community-based GDEMCIS. Similarly, Cox proportional hazard regression analysis for time to reversion indicated that recruitment from hospital-based CREDOS exhibited hazard ratio of 0.34 (95% CI, 0.20-0.59), as compared to recruitment from community-based GDEMCIS. CONCLUSION The present study demonstrated that even after the matching process and adjustments for baseline covariates, recruitment source greatly affected the course of mild cognitive impairment.