Papers by Irawan Satriotomo
Experimental Neurology, Sep 1, 2012
Acute intermittent hypoxia (AIH) initiates plasticity in respiratory motor control, including phr... more Acute intermittent hypoxia (AIH) initiates plasticity in respiratory motor control, including phrenic long term facilitation (pLTF). Since pLTF is enhanced by preconditioning with repetitive exposure to AIH (rAIH), we hypothesized that a rAIH protocol consisting of 3 AIH exposures per week for 10 weeks (3×wAIH; AIH: 10, 5-min episodes of 10.5% O 2 ; 5-min normoxic intervals) would enhance expression of molecules that play key roles in pLTF within the phrenic motor nucleus. Immunohistochemical analyses revealed that 3×wAIH for 10 weeks increased serotonin terminal density in the C4 phrenic motor nucleus and serotonin 2A (5-HT 2A) receptor expression in presumptive phrenic motor neurons. Immunoreactive brain derived neurotrophic factor (BDNF) and its high affinity receptor (TrkB) also increased following 3×wAIH. 3×wAIH also increased expression of another hypoxia-sensitive growth factor known to elicit phrenic motor facilitation, vascular endothelial growth factor (VEGF), and its receptor (VEGFR-2). Kinases "downstream" from TrkB and VEGFR-2 were up-regulated in or near presumptive phrenic motor neurons, including phosphorylated extracellular-signal regulated kinase (p-ERK) and protein kinase B (p-AKT). Thus, 3×wAIH up-regulates neurochemicals known to be associated with phrenic motor plasticity. Since 3×wAIH upregulates pro-plasticity molecules without evidence for CNS pathology, it may be a useful therapeutic tool in treating disorders that cause respiratory insufficiency, such as spinal injury or motor neuron disease.
Annals of the New York Academy of Sciences, Jun 1, 2010
Plasticity is a fundamental property of the neural system controlling breathing. One frequently s... more Plasticity is a fundamental property of the neural system controlling breathing. One frequently studied model of respiratory plasticity is long-term facilitation of phrenic motor output (pLTF) following acute intermittent hypoxia (AIH). pLTF arises from spinal plasticity, increasing respiratory motor output through a mechanism that requires new synthesis of brain derived neurotrophic factor (BDNF), activation of its high affinity receptor, tropomyosin-related kinase B (TrkB) and extracellular-related kinase (ERK) mitogen-activated protein (MAP) kinase signaling in or near phrenic motor neurons. Since intermittent hypoxia induces spinal plasticity, we are exploring the potential to harness repetitive AIH as a means of inducing functional recovery in conditions causing respiratory insufficiency, such as cervical spinal injury. Since repetitive AIH induces phenotypic plasticity in respiratory and motor neurons, it may restore respiratory motor function in patients with incomplete spinal injury.
Bali Medical Journal, Oct 1, 2022
Introduction: Lavender essential oils (LEO) have been known to have relaxing effects, improve moo... more Introduction: Lavender essential oils (LEO) have been known to have relaxing effects, improve mood, and treat anxiety, but the effect on multiple organ stress concurrently is unknown. This multiorgan stress is related to depression can be caused by chronic psychological stress due to excessive cortisol levels and can lead to organ damage. This study analyzed LEO in preventing depression and multiorgan failure using intraperitoneal injection of corticosteroids in animal-model. Methods: Rats (Rattus norvegicus) Wistar strain, male, aged 7-8 weeks were involved in this study. Depression in animalmodel is defined by immobilization using tail suspension test and anhedonia using sucrose preference test. LEO 5% was diluted in virgin coconut oils as vehicle. Serum cortisol was analyzed using enzyme-linked immunosorbent assay (ELISA). Organs were extracted and processed using hematoxylin eosin staining. Results: The results of this study indicate that LEO was able to prevent damage to the glial cells, myocardiac cells, and gastrointestinal mast cells infiltration, but not to the hepatocytes and renal cells damage. LEO also induced behavioral activation as improvement of depression, but anhedonia was still remained. Conclusion: The effect of LEO is to prevent the increase in blood cortisol levels, thus reduce the reactivity of depressed individuals to stress, although the individual still has anhedonia as a residual symptoms.
The effects of a short-term ethanol treatment on hippocampus have been studied in mice exhibiting... more The effects of a short-term ethanol treatment on hippocampus have been studied in mice exhibiting intoxication signs. The alterations of neurons and astrocytes as well as quantitative changes of calbindin D28k-immunoreactivity and glial fibrillary acidic proteinimmunoreactivity (GFAP-IR) in selected regions of the dorsal hippocampus were examined using anti-calbindin and anti-GFAP monoclonal anti-body (mAb), respectively. The administration of 6% (v / v) ethanol during first week led to the neuronal death and decrease of the total number of calbindin-IR neurons in the examined brain regions. Moreover, the calbindin positive neurons were shown to have diminished processes following short-term ethanol exposure. These neuronal changes were associated with the increase of the GFAP-IR astrocytes. Hypertrophy of cell bodies and cytoplasmic processes of reactive astrocytes were also seen. In addition, dense, thick and highly-stained GFAP-IR cells with long processes in granular cell layer appeared entering into molecular layer of dentate gyrus. In agreement with the discrepancy percentage of neuronal cell loss and increase of reactive astrocytes detected by calbindin and GFAP-IR using image quantitative analysis, the regional differences in the vulnerability to the neurotoxic effects following short-term ethanol exposure were found: CA3.CA2.CA1.DG. These findings also illustrate the importance of correlation between calbindin and GFAP-IR when determining the morphological alteration of neuron and astroglial following short-term ethanol treatment. The disruption of calbindin and GFAP could affect neuronal-astroglial interaction, resulting in disturbance of behaviors dependent on hippocampus.
Experimental Neurology, Nov 1, 2015
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characte... more Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron death. Since most ALS patients succumb to ventilatory failure from loss of respiratory motor neurons, any effective ALS treatment must preserve and/or restore breathing capacity. In rats over-expressing mutated superoxide dismutase-1 (SOD1 G93A), the capacity to increase phrenic motor output is decreased at disease end-stage, suggesting imminent ventilatory failure. Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a form of spinal respiratory motor plasticity with potential to restore phrenic motor output in clinical disorders that compromise breathing. Since pLTF requires NADPH oxidase activity and reactive oxygen species (ROS) formation, it is blocked by NADPH oxidase inhibition and SOD mimetics in normal rats. Thus, we hypothesized that SOD1 G93A (mutant; MT) rats do not express AIH-induced pLTF due to over-expression of active mutant superoxide dismutase-1. AIH-induced pLTF and hypoglossal (XII) LTF were assessed in young, pre-symptomatic and end-stage anesthetized MT rats and age-matched wild-type littermates. Contrary to predictions, pLTF and XII LTF were observed in MT rats at all ages; at end-stage, pLTF was actually enhanced. SOD1 levels were elevated in young and pre-symptomatic MT rats, yet superoxide accumulation in putative phrenic motor neurons (assessed with dihydroethidium) was unchanged; however, superoxide accumulation significantly decreased at end-stage. Thus, compensatory mechanisms appear to maintain ROS homoeostasis until late in disease progression, preserving AIH-induced respiratory plasticity. Following intrathecal injections of an NADPH oxidase inhibitor (apocynin; 600µM; 12µL), pLTF was abolished in pre-symptomatic, but not end-stage MT rats, demonstrating that pLTF is NADPH oxidase dependent in pre-symptomatic, but NADPH oxidase
The Journal of Physiology, Apr 29, 2009
Phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is a form of spi... more Phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is a form of spinal, serotonin-dependent synaptic plasticity that requires reactive oxygen species (ROS) formation. We tested the hypothesis that spinal NADPH oxidase activity is a necessary source of ROS for pLTF. Sixty minutes post-AIH (three 5-min episodes of 11% O2, 5 min intervals), integrated phrenic and hypoglossal (XII) nerve burst amplitudes were increased from baseline, indicative of phrenic and XII LTF. Intrathecal injections (∼C4) of apocynin or diphenyleneiodonium chloride (DPI), two structurally and functionally distinct inhibitors of the NADPH oxidase complex, attenuated phrenic, but not XII, LTF. Immunoblots from soluble (cytosolic) and particulate (membrane) fractions of ventral C4 spinal segments revealed predominantly membrane localization of the NADPH oxidase catalytic subunit, gp91phox, whereas membrane and cytosolic expression were both observed for the regulatory subunits, p47phox and RAC1. Immunohistochemical analysis of fixed tissues revealed these same subunits in presumptive phrenic motoneurons of the C4 ventral horn, but not in neighbouring astrocytes or microglia. Collectively, these data demonstrate that NADPH oxidase subunits localized within presumptive phrenic motoneurons are a major source of ROS necessary for AIH-induced pLTF. Thus, NADPH oxidase activity is a key regulator of spinal synaptic plasticity, and may be a useful pharmaceutical target in developing therapeutic strategies for respiratory insufficiency in patients with, for example, cervical spinal injury.
Journal of Pharmacology and Experimental Therapeutics, Dec 13, 2006
Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription fac... more Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone following SCI in adult rats. Both pioglitazone and rosiglitazone (1.5 mg/ Kg; i.p.; 4 doses at 5 min, 12h, 24h, and 48h) significantly decreased the lesion size (by 57 to 68%, p<0.05), motor neuron loss (by 3 to 10 fold, p<0.05), myelin loss (by 66 to 75%, p<0.05), astrogliosis (by 46 to 61%, p<0.05) and microglial activation (by 59 to 78%, p<0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over vehicle group; p<0.05); but the treatment was effective only when the first injection was given by 2h after SCI. At 28-days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p<0.05) in the pioglitazone group compared to vehicle group. At 6h after SCI, pioglitazone group showed significantly less induction of inflammatory genes (IL6 by 83%, IL1β by 87%, MCP1 by 75%, ICAM1 by 84% and Egr1 by 67%) compared to vehicle group (p<0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat-shock proteins and anti-oxidant enzymes. Pretreatment with a PPARγ antagonist GW9662 prevented the neuroprotection induced by pioglitazone.
Congenital Anomalies, Sep 1, 2002
... Miki T. Department of Anatomy, Kagawa Medical University. Gu H. Department of Anatomy, Kagawa... more ... Miki T. Department of Anatomy, Kagawa Medical University. Gu H. Department of Anatomy, Kagawa Medical University. Matsumoto Y. Department of Anatomy, Kagawa Medical University.Satriotomo I. Department of Anatomy, Kagawa Medical University. ...
Congenital Anomalies, Sep 1, 2001
... Medicine, Kagawa Medical University. Satriotomo I. Department of Anatomy, Faculty of Medicine... more ... Medicine, Kagawa Medical University. Satriotomo I. Department of Anatomy, Faculty of Medicine, Kagawa Medical University. Gu H. Department of Anatomy, Faculty of Medicine, Kagawa Medical University. Matsumoto Y. Department ...
The FASEB Journal, Apr 1, 2010
Brain Research, Nov 1, 1999
Morphological changes of the suprachiasmatic nucleus (SCN) of the hypothalamus were investigated ... more Morphological changes of the suprachiasmatic nucleus (SCN) of the hypothalamus were investigated in mice exhibiting intoxication signs of stages 2 or 3 after a short application term of 6% ethanol. Alterations in glial cells and neurons were examined using anti-glial fibrillary acidic protein (GFAP) and anti-calbindin D28k monoclonal antibody, respectively. The results revealed that short-term ethanol exposure led to strong expression of GFAP-immunoreactivity (GFAP-IR) in the dorsomedial part of the SCN. Furthermore, GFAP-IR astrocytes showed an increase in number and hypertrophy with longer processes. However, calbindin D28k-IR neurons were apparently little changed in the SCN. It is concluded that neuroadaptive response of astrocytes could occur before the neurotoxic effects emerge on neurons on the SCN.
International Journal of Andrology, Jan 5, 2002
Light microscopical studies on the uptake of blood-borne horseradish peroxidase (HRP) in large ar... more Light microscopical studies on the uptake of blood-borne horseradish peroxidase (HRP) in large areas of the testis have been scarce because of the difficulty of staining HRP in testes with well-preserved morphology. However, observation of exogenous HRP in all areas of the testis enables detection of regional tissue injury induced by toxic chemicals or immunization. In the present study, the localization of blood-borne HRP in the murine testis was investigated light microscopically using plastic-embedded testes and post-embedding histochemical methods. Mice were injected intravenously with HRP, and then perfused with 2.5% glutaraldehyde and 3% paraformaldehyde in 0.1 M phosphate buffer. The fixed testes were immediately removed, dehydrated, and then embedded in plastic without cutting them into small pieces. The prepared sections treated by the diaminobenzidine method exhibited intense HRP activity with well-preserved testis morphology. It was noted that many interstitial macrophages had endocytosed HRP. In particular, HRP-endocytosing macrophages were concentrated around the tubuli recti. The testicular capsule, containing many lymphatic capillaries and vessels, was also loaded with HRP. In the subcapsular interstitium, free HRP in the lymph space accumulated, but the staining intensity was weak compared to that in testicular macrophages. No HRP infiltration into the lumen of the seminiferous tubules was observed at the light microscope level; however, HRP staining was detected in tubular walls and epithelial cells lining the rete testis and tubuli recti, indicating that these regions are permeable to HRP.
The Journal of Neuroscience, Apr 25, 2012
Erythropoietin (EPO) is typically known for its role in erythropoiesis but is also a potent neuro... more Erythropoietin (EPO) is typically known for its role in erythropoiesis but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by hypoxia-inducible factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Because EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague Dawley rats that EPO and its receptor, EPO-R, are expressed in identified phrenic motor neurons. Intrathecal EPO at C4 elicits long-lasting pMF; integrated phrenic nerve burst amplitude increased Ͼ90 min after injection (63 Ϯ 12% baseline 90 min after injection; p Ͻ 0.001). EPO increased phosphorylation (and presumed activation) of ERK (1.6-fold vs controls; p Ͻ 0.05) in phrenic motor neurons; EPO also increased pAkt (1.6-fold vs controls; p Ͻ 0.05). EPO-induced pMF was abolished by the MEK/ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene] and the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one], demonstrating that ERK MAP kinases and Akt are both required for EPOinduced pMF. Pretreatment with U0126 and LY294002 decreased both pERK and pAkt in phrenic motor neurons (p Ͻ 0.05), indicating a complex interaction between these kinases. We conclude that EPO elicits spinal plasticity in respiratory motor control. Because EPO expression is hypoxia sensitive, it may play a role in respiratory plasticity in conditions of prolonged or recurrent low oxygen.
Spine, Nov 1, 2006
Laboratory investigation of pain behavior following spinal cord injury. To explore changes in the... more Laboratory investigation of pain behavior following spinal cord injury. To explore changes in the spinal cord expression of nociceptive genes following spinal cord injury (SCI) as they relate to the manifestation of pain behavior in rats. Neuropathic pain following SCI is common, disabling, and largely untreatable. In peripheral nerve injury models, bradykinin B1 and vanilloid 1 (TRPV-1) receptor activity is associated with neuropathic pain behavior. We sought to examine the role of these gene products in SCI-mediated pain. Rats were subjected to SCI using the MASCIS impactor. Animals were tested preinjury and at regular intervals postinjury for the appearance of thermal hyperalgesia using a hind limb withdrawal latency test. The expression of B1 and TRPV-1 genes was assessed using real-time polymerase chain reaction. Immunohistochemistry was used to localize the B1 and TRPV-1 receptors within the spinal cord. Greater than twofold increases in the expression of the B1 and TRPV-1 genes were detected in the injured region of the spinal cord in animals exhibiting hyperalgesia compared with animals with SCI that did not display hyperalgesia. Immunohistochemical staining revealed that both receptor types were largely localized to the dorsal horn. Staining for TRPV-1 receptors decreased while that for B1 receptors increased in all of the injured animals when compared with sham-operated controls. B1 and TRPV-1 receptor genes are overexpressed in the injured spinal cord of animals manifesting thermal hyperalgesia following SCI compared with similarly injured animals without hyperalgesia. This finding is consistent with past work regarding the role of these receptors in nociception and indicates that ongoing modifiable processes are occurring in the spinal cord that lead to clinical pain syndromes.
Journal of Neurosurgery, Sep 1, 2007
Object Neurogenesis continues throughout the life of mammals in the subventricular zone (SVZ) of ... more Object Neurogenesis continues throughout the life of mammals in the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus (DG) of the hippocampus. The authors tested the potential of the neuropeptide substance P (SP) acting via the neurokinin-1 receptor (NK1R) in promoting the proliferation of adult rat neural progenitor cells (NPCs). Methods Focal ischemia was induced in spontaneously hypertensive rats by transient middle cerebral artery occlusion. Substance P and the NK1R antagonist L-703,606 were infused into the lateral ventricles of rats by using Alzet osmotic minipumps. Progenitor cell proliferation was evaluated with immunostaining for bromodeoxyuridine (BrdU) and immature neural marker doublecortin (DCX). Neurospheres were cultured from the SVZ of adult rats. Results Under in vitro conditions, SP (0.01–10 μmol/L) increased the proliferation of cultured NPCs, with a peak increase of 52 ± 7% at 0.1 μmol/L. Substance P (0.1 μmol/L) continuously increased NPC proliferation from 6 hours to 5 days, which was prevented by L-703,606 (by 69–98%). The cultured NPCs expressed both SP and NK1R proteins, indicating that these effects are receptor specific. Continuous infusion of SP (1 μmol/L) into the lateral ventricles for 5 days significantly increased the number of proliferating NPCs (cells positive for both BrdU and DCX) in both the SVZ (by 173 ± 24%, p &lt; 0.05) and DG (by 82 ± 12%, p &lt; 0.05) in adult rats; however, infusion of L-703,606 (10 μmol/L) significantly prevented the postischemic induction of NPC proliferation in both the SVZ (by 84 ± 6%, p &lt; 0.05) and DG (by 63 ± 7%, p &lt; 0.05). Conclusions Data in these studies indicated that SP plays a role in normal and ischemia-induced neurogenesis in the adult brain and thus could help central nervous system plasticity following injury.
MCBS (Molecular and Cellular Biomedical Sciences), Mar 1, 2018
Background: It is known that eye enucleation causes various morphological and functional alterati... more Background: It is known that eye enucleation causes various morphological and functional alterations in the central nervous system (CNS). The purpose of this study was to examine the sub-chronic effects of monocular enucleation on the distribution of the calcium binding proteins calbindin D28k (CB) and parvalbumin (PV) as well as the glial fibrillary acidic protein (GFAP) immunoreactivity in the superior colliculus (SC) of Wistar rats. Materials and Methods: Thirty young adult (8 weeks) male Wistar rats from SLC (Shizuoka, Japan), weighing 200-250 grams, were housed in separate cages under controlled conditions with a constant temperature kept in 12:12 light/dark cycle and ad libitum water and food. In this study the rats were divided into two groups, a control and an enucleated groups. The experimental group received unilateral eye enucleation and was allowed 1, 4 or 12 weeks recovery before sacrificed. Results: Unilateral enucleation over a period of 1 week or more caused a decrease in the number CB-immunoreactive (CB-IR) neurons. This loss was associated with an increase in GFAP-IR astrocytes in the superficial gray layer and the optic layer of the SC with contralateral side predominance. In addition, the CB-IR neurons illustrated a smaller soma and poor dendritic arborization. Conversely, the GFAP-IR astrocytes were hypertrophied with longer foot processes on the contralateral side of enucleation. Interestingly, the number of PV-IR neurons was elevated for up to 4 weeks in enucleated rats versus shamoperated rats. Conclusion: This study demonstrates the importance of calcium-binding protein homeostasis and reversible glial response for maintaining variability of neuronal function in sub-cortical visual centers following optic nerve deafferentation.
The FASEB Journal, Apr 1, 2010
International Journal of Andrology, Jun 1, 2001
The right gonadal vein (GV testicular vein in men, ovarian vein in women) usually drains into the... more The right gonadal vein (GV testicular vein in men, ovarian vein in women) usually drains into the inferior vena cava (IVC) while the left gonadal vein drains into the left renal vein (RV). This anatomical difference induces relatively weak haemodynamics in the left testicular vein (TV) and is considered to be a cause of a left varicocele. In textbooks on embryology, it has been documented that bilateral supracardinal veins (origin of right and left IVC) and the subcardinal sinus (origin of RVs and GVs) symmetrically develop during early embryogenesis. However, persistence and regression of the right and left supracardinal veins, respectively, results in drainage of the left GV into the ipsilateral RV. A double IVC (DIVC) commonly originates from a failure of disappearance of the left supracardinal vein. Although there have been a considerable number of case reports on DIVC, little attention has been paid to the anatomy of the left GV in such cases. We report here an autopsy case, a 72-year-old Japanese man, with a DIVC. This case belongs to type BC of McClure and Butler's classi®cation. In this case, it was observed that the right TV drained into the con¯uence of the right IVC with the ipsilateral RV, while the left TV drained into the left RV in spite of the presence of the left IVC. This case indicates that the embryonic anastomosis point between the subcardinal sinus and the supracardinal vein on the left side is different from that on the right side. Statistical analysis of many case reports of DIVC also suggests that the bilateral supracardinal veins tend to asymmetrically anastomose with the subcardinal sinus during embryogenesis. These data imply that drainage of the left GV into the ipsilateral RV leads to regression of the left supracardinal vein but also to asymmetrical anastomosis between the supracardinal veins and the subcardinal sinus.
The FASEB Journal, Apr 1, 2009
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Papers by Irawan Satriotomo