Displaying publications 1 - 20 of 36 in total

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  1. 5-Fluorouracil loaded magnetic cellulose bionanocomposites for potential colorectal cancer treatment
    Yusefi M, Lee-Kiun MS, Shameli K, Teow SY, Ali RR, Siew KK, et al.
    Carbohydr Polym, 2021 Dec 01;273:118523.
    PMID: 34560940 DOI: 10.1016/j.carbpol.2021.118523
    Magnetic polymer nanocomposites are inherently multifunctional and harbor assorted physiochemical actions for applications thereof as novel drug nanocarriers. Herein, Fe3O4-nanoparticles were supported on rice straw cellulose for 5-fluorouracil carrier abbreviated as MC/5-FU for potential colorectal cancer treatments. Several analyses indicated the multifunctional properties of MC/5-FU bionanocomposites. Transmission and scanning electron microscopy study demonstrated that Fe3O4 nanofillers covered the cellulose matrix. The drug release from MC/5-FU was evaluated under various pH and temperature conditions, showing the maximum release at pH 7.4 and 44.2 °C. In in vitro anticancer assay, MC/5-FU exhibited enhanced selectivity and anticancer actions against 2D monolayer and 3D tumour spheroid models colorectal cancer cells. The anticancer effects of MC/5-FU with magnetic targeting and heat induction were also examined. This easily synthesized MC/5-FU indicated the potential in application as a low-cost drug formulation for colorectal cancer treatments.
  2. Fulltext A Biogeography-Based Optimization Algorithm Hybridized with Tabu Search for the Quadratic Assignment Problem
    Lim WL, Wibowo A, Desa MI, Haron H
    Comput Intell Neurosci, 2016;2016:5803893.
    PMID: 26819585 DOI: 10.1155/2016/5803893
    The quadratic assignment problem (QAP) is an NP-hard combinatorial optimization problem with a wide variety of applications. Biogeography-based optimization (BBO), a relatively new optimization technique based on the biogeography concept, uses the idea of migration strategy of species to derive algorithm for solving optimization problems. It has been shown that BBO provides performance on a par with other optimization methods. A classical BBO algorithm employs the mutation operator as its diversification strategy. However, this process will often ruin the quality of solutions in QAP. In this paper, we propose a hybrid technique to overcome the weakness of classical BBO algorithm to solve QAP, by replacing the mutation operator with a tabu search procedure. Our experiments using the benchmark instances from QAPLIB show that the proposed hybrid method is able to find good solutions for them within reasonable computational times. Out of 61 benchmark instances tested, the proposed method is able to obtain the best known solutions for 57 of them.
  3. Fulltext A Decade of Progress in Deep Brain Stimulation of the Subcallosal Cingulate for the Treatment of Depression
    Khairuddin S, Ngo FY, Lim WL, Aquili L, Khan NA, Fung ML, et al.
    J Clin Med, 2020 Oct 12;9(10).
    PMID: 33053848 DOI: 10.3390/jcm9103260
    Major depression contributes significantly to the global disability burden. Since the first clinical study of deep brain stimulation (DBS), over 406 patients with depression have now undergone this neuromodulation therapy, and 30 animal studies have investigated the efficacy of subgenual cingulate DBS for depression. In this review, we aim to provide a comprehensive overview of the progress of DBS of the subcallosal cingulate in humans and the medial prefrontal cortex, its rodent homolog. For preclinical animal studies, we discuss the various antidepressant-like behaviors induced by medial prefrontal cortex DBS and examine the possible mechanisms including neuroplasticity-dependent/independent cellular and molecular changes. Interestingly, the response rate of subcallosal cingulate Deep brain stimulation marks a milestone in the treatment of depression. DBS among patients with treatment-resistant depression was estimated to be approximately 54% across clinical studies. Although some studies showed its stimulation efficacy was limited, it still holds great promise as a therapy for patients with treatment-resistant depression. Overall, further research is still needed, including more credible clinical research, preclinical mechanistic studies, precise selection of patients, and customized electrical stimulation paradigms.
  4. Fulltext Antidepressive Mechanisms of Probiotics and Their Therapeutic Potential
    Yong SJ, Tong T, Chew J, Lim WL
    Front Neurosci, 2019;13:1361.
    PMID: 32009871 DOI: 10.3389/fnins.2019.01361
    The accumulating knowledge of the host-microbiota interplay gives rise to the microbiota-gut-brain (MGB) axis. The MGB axis depicts the interkingdom communication between the gut microbiota and the brain. This communication process involves the endocrine, immune and neurotransmitters systems. Dysfunction of these systems, along with the presence of gut dysbiosis, have been detected among clinically depressed patients. This implicates the involvement of a maladaptive MGB axis in the pathophysiology of depression. Depression refers to symptoms that characterize major depressive disorder (MDD), a mood disorder with a disease burden that rivals that of heart diseases. The use of probiotics to treat depression has gained attention in recent years, as evidenced by increasing numbers of animal and human studies that have supported the antidepressive efficacy of probiotics. Physiological changes observed in these studies allow for the elucidation of probiotics antidepressive mechanisms, which ultimately aim to restore proper functioning of the MGB axis. However, the understanding of mechanisms does not yet complete the endeavor in applying probiotics to treat MDD. Other challenges remain which include the heterogeneous nature of both the gut microbiota composition and depressive symptoms in the clinical setting. Nevertheless, probiotics offer some advantages over standard pharmaceutical antidepressants, in terms of residual symptoms, side effects and stigma involved. This review outlines antidepressive mechanisms of probiotics based on the currently available literature and discusses therapeutic potentials of probiotics for depression.
  5. Fulltext Audit of perioperative blood transfusion
    Choy YC, Lim WL, Ng SH
    Med J Malaysia, 2007 Oct;62(4):299-302.
    PMID: 18551933 MyJurnal
    The main goal of perioperative transfusion is to reduce the morbidity and mortality associated with inadequate delivery of oxygen to the tissues during surgery. In this audit, the primary trigger for transfusion was clinical anaemia assessed by examination of a patient's conjunctiva [40.7%] followed by estimation of blood loss of greater 20% of total blood volume [29.3%]. Haemoglobin estimation in the operation theater was not done in 45.9% of studied patients and only 7.8% patients had transfusion based on this criteria. A common practice is to transfuse blood for hypovolaemia. This was the indication for blood transfusion in 96 patients (7.8%). Inappropriate use of blood in this way has led to wastage of a valuable resource and exposed patients to potential risks of unwanted side effects. Analysis of haemoglobin estimation at recovery room showed 32% of patient with co-morbidities had Hb > 10 gm% while 65% and 29.5% of patients without co-morbidities had Hb > 8 gm% and 10 gm% respectively. This reflects the practice of anaesthetists in maintaining a target of Hb of 10 gm% for both groups of patients while a target of 8 gm% is still relatively safe for patients with good cardiovascular reserves. This has resulted in signifant use of homologous blood which will certainly burden the blood bank and increase the cost of healthcare.
  6. Behavioural responses of anxiety in aversive and non-aversive conditions between young and aged Sprague-Dawley rats
    Hiew LF, Khairuddin S, Aquili L, Koh J, Fung ML, Lim WL, et al.
    Behav Brain Res, 2020 05 15;385:112559.
    PMID: 32097707 DOI: 10.1016/j.bbr.2020.112559
    Measures of anxiety in behavioural tests remain largely unclear even decades after their establishment. Differences in the severity of anxiety measured by anxiety tests is an important issue that must be addressed. To test the hypothesis that the addition of light as an aversive stimulus will elicit a difference in behaviour between aged and young animals, we compared the responses of aged and young animals in the home cage emergence test (HCET) and elevated plus maze (EPM), in high aversive bright light and low aversive dim light conditions. In the HCET, our results demonstrated that young animals escaped with shorter latency and greater frequency than aged animals in both bright and dim light conditions, indicating that young animals display greater exploratory tendencies than aged animals. In the EPM, bright light conditions induced anxiogenic effects in both age groups. Interestingly, two-way ANOVA showed a significant interaction effect of age and light on the number of entries into the open arms of the EPM as well as frequency of escape in the HCET. These results show that the addition of light as an aversive stimulus in the EPM and HCET produced different responses in aged versus young animals in each test. In conclusion, significant interactions between age and light affected aged and young animals differently in the HCET and EPM, indicating that the two tests measure different aspects of anxiety.
  7. Benefits of PECS Block as Part of the Enhanced Recovery After Surgery (ERAS) Protocol for Breast Cancer Surgery in an Asian Institution: A Retrospective Cohort Study
    Diana K, Teh MS, Islam T, Lim WL, Beh ZY, Taib NAM
    World J Surg, 2023 Mar;47(3):564-572.
    PMID: 36599951 DOI: 10.1007/s00268-022-06881-7
    INTRODUCTION: Regional analgesia techniques have been increasingly used for post-operative pain management following mastectomy. We aim to evaluate analgesic benefits of pectoral nerve (PECS2) block incorporated as part of the enhanced recovery after surgery (ERAS) protocol in patients undergoing mastectomy in University Malaya Medical Centre, Malaysia.

    MATERIAL AND METHODS: A single centre, cohort study evaluating 335 women who have undergone unilateral mastectomy between January 2017 and March 2020 in Malaysia. Regional anaesthesia were given pre-operatively via ultrasound guided pectoral and intercostal nerves block (PECSII).

    RESULTS: Utilization of regional anaesthesia increased from 11% in 2017 to 43% in 2020. Types and duration of surgeries were comparable. Opiod consumption was 3 mg lower in those who had PECS2 block ((27 [24-30] mg), in comparison with those who received general anaesthesia only (30 [26-34] mg), p 

  8. Breastfeeding at 6 weeks and predictive factors
    Chye JK, Zain Z, Lim WL, Lim CT
    J Trop Pediatr, 1997 10;43(5):287-92.
    PMID: 9364127 DOI: 10.1093/tropej/43.5.287
    Despite the numerous changes made in accordance with the Baby Friendly Hospital Initiative at the University Hospital, Kuala Lumpur, the low rates of breastfeeding have persisted. This study aims to examine the current trend in infant feeding, and the influences of some perinatal and sociodemographic factors on breastfeeding. Five-hundred mothers with singleton pregnancies and healthy infants were interviewed at 6 weeks post-partum. Only 124 (25 per cent) mothers were practising exclusive breastfeeding (EBF), and 132 (26 per cent) mothers were using exclusive infant formula feeding (EIF). On logistic regression analyses, mothers who followed EBF were more likely to have had antenatal plans to breastfeed (Odds ratio 2.44, 95 per cent confidence interval 1.75-3.45), not in paid employment post-natally (OR 1.76, 95 per cent CI 1.31-2.36), of older age group (> 27 years) (OR 1.48, 95 per cent CI 1.13-1.93), had female infants (OR 1.38, 95 per cent CI 1.05-1.80) and of Indian ethnicity (compared to Chinese) (OR 3.87, 95 per cent CI 2.16-6.89). Breastfeeding difficulties were associated with decreased odds of EBF (OR 0.21, 95 per cent CI 0.13-0.34). Parental education, fathers' ages and incomes, primigravida status, Caesarean section, present of episiotomy, late first breastfeed, phototherapy, and length of hospital stay were not significant predictors of failure of EBF. In comparison, predictive factors for increased use of EIF were mothers who have had breastfeeding difficulties, < or = 9 years of schooling, and of Chinese descent. In conclusions, the overall rate of EBF by 6 weeks of age in infants born in this urban hospital had remained poor. The adverse factors for EBF identified in this study warrant further in-depth studies to determine effective ways of improving EBF rates.
  9. Comparison of propofol and methohexitone as an induction agent in anaesthesia for electroconvulsive therapy
    Lim SK, Lim WL, Elegbe EO
    West Afr J Med, 1996 Oct-Dec;15(4):186-9.
    PMID: 9020593
    30 patients who received electroconvulsive therapy were anaesthetized with either Propofol or Methohexitone in a randomized cross-over study. Recovery times were shorter in those who received Propofol. The decrease in diastolic pressure after induction was greater with Propofol than with Methohexitone. There was a greater increase in the blood pressure after the electroconvulsive therapy in those who received Methohexitone. The duration of convulsion was similar for both agents.
  10. Fulltext Current Progress in Tendon and Ligament Tissue Engineering
    Lim WL, Liau LL, Ng MH, Chowdhury SR, Law JX
    Tissue Eng Regen Med, 2019 Dec;16(6):549-571.
    PMID: 31824819 DOI: 10.1007/s13770-019-00196-w
    BACKGROUND: Tendon and ligament injuries accounted for 30% of all musculoskeletal consultations with 4 million new incidences worldwide each year and thus imposed a significant burden to the society and the economy. Damaged tendon and ligament can severely affect the normal body movement and might lead to many complications if not treated promptly and adequately. Current conventional treatment through surgical repair and tissue graft are ineffective with a high rate of recurrence.

    METHODS: In this review, we first discussed the anatomy, physiology and pathophysiology of tendon and ligament injuries and its current treatment. Secondly, we explored the current role of tendon and ligament tissue engineering, describing its recent advances. After that, we also described stem cell and cell secreted product approaches in tendon and ligament injuries. Lastly, we examined the role of the bioreactor and mechanical loading in in vitro maturation of engineered tendon and ligament.

    RESULTS: Tissue engineering offers various alternative ways of treatment from biological tissue constructs to stem cell therapy and cell secreted products. Bioreactor with mechanical stimulation is instrumental in preparing mature engineered tendon and ligament substitutes in vitro.

    CONCLUSIONS: Tissue engineering showed great promise in replacing the damaged tendon and ligament. However, more study is needed to develop ideal engineered tendon and ligament.

  11. Distribution of neuronal nitric oxide synthase immunoreactivity in adult male Sprague-Dawley rat brain
    Chong PS, Poon CH, Fung ML, Guan L, Steinbusch HWM, Chan YS, et al.
    Acta Histochem, 2019 Nov;121(8):151437.
    PMID: 31492421 DOI: 10.1016/j.acthis.2019.08.004
    Neuronal NOS (nNOS) accounts for most of the NO production in the nervous system that modulates synaptic transmission and neuroplasticity. Although previous studies have selectively described the localisation of nNOS in specific brain regions, a comprehensive distribution profile of nNOS in the brain is lacking. Here we provided a detailed morphological characterization on the rostro-caudal distribution of neurons and fibres exhibiting positive nNOS-immunoreactivity in adult Sprague-Dawley rat brain. Our results demonstrated that neurons and fibres in the brain regions that exhibited high nNOS immunoreactivity include the olfactory-related areas, intermediate endopiriform nucleus, Islands of Calleja, subfornical organ, ventral lateral geniculate nucleus, parafascicular thalamic nucleus, superior colliculus, lateral terminal nucleus, pedunculopontine tegmental nucleus, periaqueductal gray, dorsal raphe nucleus, supragenual nucleus, nucleus of the trapezoid body, and the cerebellum. Moderate nNOS immunoreactivity was detected in the cerebral cortex, caudate putamen, hippocampus, thalamus, hypothalamus, amygdala, and the spinal cord. Finally, low NOS immunoreactivity were found in the corpus callosum, fornix, globus pallidus, anterior commissure, and the dorsal hippocampal commissure. In conclusion, this study provides a comprehensive view of the morphology and localisation of nNOS immunoreactivity in the brain that would contribute to a better understanding of the role played by nNOS in the brain.
  12. Fulltext Effect of an intensive patient educational programme on the quality of bowel preparation for colonoscopy: a single-blind randomised controlled trial
    Janahiraman S, Tay CY, Lee JM, Lim WL, Khiew CH, Ishak I, et al.
    BMJ Open Gastroenterol, 2020 05;7(1).
    PMID: 32371502 DOI: 10.1136/bmjgast-2020-000376
    OBJECTIVE: Preprocedural bowel preparation is necessary for optimal colonoscopy visualisation. However, it is challenging to achieve high-quality bowel preparation among patients scheduled for colonoscopy. This study aims to evaluate the impact of an intensive patient educational programme on the quality of bowel preparation.

    DESIGN: An accessor-blinded randomised controlled trial was carried out at the outpatient surgical clinic of a tertiary hospital. Patients were randomly assigned to the control group (received standard written and verbal instructions) or the experimental group (received an intensive and structured educational programme). All subjects completed a questionnaire before colonoscopy to assess their compliance, acceptability, and tolerability towards bowel preparation regime. Quality of bowel preparation was determined using the Boston Bowel Preparation Scale (BBPS).

    RESULTS: A total of 300 subjects who fulfilled the inclusion criteria were recruited. The experimental group had a significantly higher proportion of good quality bowel preparation than the control group (98.7% vs 52.3%, p<0.001). The median total BBPS score was also significantly higher in the experimental group (8 vs 5, p<0.001). Factors associated with good quality of bowel preparation included educational programme (OR: 22.79, 95% CI: 4.23 to 122.85, p<0.001), compliance to bowel cleansing agent (OR: 24.98, 95% CI 3.12 to 199.71, p<0.001), very difficult acceptability of preparation (OR: 0.11, 95% CI 0.03 to 0.38, p<0.001), tolerability towards bowel preparation (OR: 4.98, 95% CI 1.44 to 17.20, p<0.011) and hypomotility drugs (OR: 3.03, 95% CI 0.12 to 0.91, p<0.05).

    CONCLUSION: An intensive patient educational programme can significantly improve the quality of bowel preparation for colonoscopy.

  13. Erector spinae plane block as analgesic adjunct for traumatic rib fractures in intensive care unit
    Beh ZY, Lim SM, Lim WL, Sitaram PN
    Indian J Anaesth, 2020 Dec;64(12):1086-1089.
    PMID: 33542581 DOI: 10.4103/ija.IJA_1110_20
  14. Fatal enterovirus 71 encephalomyelitis
    Lum LC, Wong KT, Lam SK, Chua KB, Goh AY, Lim WL, et al.
    J Pediatr, 1998 Dec;133(6):795-8.
    PMID: 9842048
    During an outbreak of hand-foot-mouth disease caused by enterovirus 71 (EV-71) in 1997, 4 children presented with sudden cardiopulmonary collapse and minimal neurologic features. All children received cardiopulmonary resuscitation but died within a few hours of admission. Postmortem studies showed infection by EV-71 with extensive damage to the medulla and pons. We postulate an etiologic link between EV-71 and brainstem encephalomyelitis as the cause of pulmonary edema and death.
  15. Flavonoids and its Neuroprotective Effects on Brain Ischemia and Neurodegenerative Diseases
    Putteeraj M, Lim WL, Teoh SL, Yahaya MF
    Curr Drug Targets, 2018;19(14):1710-1720.
    PMID: 29577854 DOI: 10.2174/1389450119666180326125252
    Brain ischemia is among the leading cause of death with majority of the cases are associated with ischemic strokes. It can occur in two forms of either focal or global ischemia. Neurodegenerative disorder such as Alzheimer and Parkinson diseases is also on the rise worldwide. These disorders have common similarities; i.e. they all affecting the central nervous system with debilitating effect to the patient. In this review, we look into the promising role of flavonoids, a natural bioactive compound found abundant in vegetables, fruits and traditional herbs. Treatment with flavonoids such as curcumin, lycopene, ginsenoside, vitexin and baicalin have shown promising neuroprotective effects against ischemic-induced injury. Besides anticancer, antioxidant and immunomodulation properties, flavonoid also exerts neuroprotective effects by increases neuronal viability, increases tissue perfusion and cerebral blood flow and reduce ischemic-related apoptosis. In addition, flavonoid also exerts anti-amyloidogenic effect and reduces loss of dopaminergic neurons in the brain. These results suggesting flavonoids might be able to serve as a potential therapeutic agent in brain disorders.
  16. Fulltext Human Embryonic Stem Cell-Derived Neural Lineages as In Vitro Models for Screening the Neuroprotective Properties of Lignosus rhinocerus (Cooke) Ryvarden
    Yeo Y, Tan JBL, Lim LW, Tan KO, Heng BC, Lim WL
    Biomed Res Int, 2019;2019:3126376.
    PMID: 33204680 DOI: 10.1155/2019/3126376
    In the biomedical field, there is growing interest in using human stem cell-derived neurons as in vitro models for pharmacological and toxicological screening of bioactive compounds extracted from natural products. Lignosus rhinocerus (Tiger Milk Mushroom) is used by indigenous communities in Malaysia as a traditional medicine to treat various diseases. The sclerotium of L. rhinocerus has been reported to have medicinal properties, including various bioactivities such as neuritogenic, anti-inflammatory, and anticancer effects. This study aims to investigate the neuroprotective activities of L. rhinocerus sclerotial extracts. Human embryonic stem cell (hESC)-derived neural lineages exposed to the synthetic glucocorticoid, dexamethasone (DEX), were used as the in vitro models. Excess glucocorticoids have been shown to adversely affect fetal brain development and impair differentiation of neural progenitor cells. Screening of different L. rhinocerus sclerotial extracts and DEX on the hESC-derived neural lineages was conducted using cell viability and neurite outgrowth assays. The neuroprotective effects of L. rhinocerus sclerotial extracts against DEX were further evaluated using apoptosis assays and Western blot analysis. Hot aqueous and methanol extracts of L. rhinocerus sclerotium promoted neurite outgrowth of hESC-derived neural stem cells (NSCs) with negligible cytotoxicity. Treatment with DEX decreased viability of NSCs by inducing apoptosis. Coincubation of L. rhinocerus methanol extract with DEX attenuated the DEX-induced apoptosis and reduction in phospho-Akt (pAkt) level in NSCs. These results suggest the involvement of Akt signaling in the neuroprotection of L. rhinocerus methanol extract against DEX-induced apoptosis in NSCs. Methanol extract of L. rhinocerus sclerotium exhibited potential neuroprotective activities against DEX-induced toxicity in hESC-derived NSCs. This study thus validates the use of human stem cell-derived neural lineages as potential in vitro models for screening of natural products with neuroprotective properties.
  17. Job insecurity and psychological distress during the COVID-19 outbreak: The moderating role of perceived supervisor support among hotel employees in Malaysia
    Appannan JS, Maheswaran L, Raimee N, Lim WL, Amran FH
    Work, 2022;73(4):1135-1145.
    PMID: 36057808 DOI: 10.3233/WOR-211467
    BACKGROUND: Millions of employees were laid off during the COVID-19 pandemic. The hospitality industry has been gravely hit by this crisis.

    OBJECTIVE: Drawing from the theory of conservation of resources (COR), our study aims to examine possible factors that influence turnover intention among hotel employees.

    METHODS: The hypotheses were tested on 141 hotel employees from Klang Valley, Malaysia. Data were collected by means of questionnaires, purposive sampling was employed, and PLS-SEM was used in performing the data analyses.

    RESULTS: Job insecurity and psychological distress were found to be the potent antecedent of turnover intention. In contrast, the role of perceived supervisor support did not significantly moderate the effects of both job insecurity and psychological distress on the quitting intention.

    CONCLUSION: Re-looking at existing policies and leadership styles may be fruitful in ensuring the sustainability path of an organization. This is pivotal in growing back the entire hospitality industry that has gravely affected by COVID-19.

  18. Fulltext Kisspeptin Activates Ankrd 26 Gene Expression in Migrating Embryonic GnRH Neurons
    Soga T, Lim WL, Khoo AS, Parhar IS
    Front Endocrinol (Lausanne), 2016;7:15.
    PMID: 26973595 DOI: 10.3389/fendo.2016.00015
    Kisspeptin, a newly discovered neuropeptide, regulates gonadotropin-releasing hormone (GnRH). Kisspeptins are a large RF-amide family of peptides. The kisspeptin coded by KiSS-1 gene is a 145-amino acid protein that is cleaved to C-terminal peptide kisspeptin-10. G-protein-coupled receptor 54 (GPR54) has been identified as a kisspeptin receptor, and it is expressed in GnRH neurons and in a variety of cancer cells. In this study, enhanced green fluorescent protein (EGFP) labeled GnRH cells with migratory properties, which express GPR54, served as a model to study the effects of kisspeptin on cell migration. We monitored EGFP-GnRH neuronal migration in brain slide culture of embryonic day 14 transgenic rat by live cell imaging system and studied the effects of kisspeptin-10 (1 nM) treatment for 36 h on GnRH migration. Furthermore, to determine kisspeptin-induced molecular pathways related with apoptosis and cytoskeletal changes during neuronal migration, we studied the expression levels of candidate genes in laser-captured EGFP-GnRH neurons by real-time PCR. We found that there was no change in the expression level of genes related to cell proliferation and apoptosis. The expression of ankyrin repeat domain-containing protein (ankrd) 26 in EGFP-GnRH neurons was upregulated by the exposure to kisspeptin. These studies suggest that ankrd 26 gene plays an unidentified role in regulating neuronal movement mediated by kisspeptin-GPR54 signaling, which could be a potential pathway to suppress cell migration.
  19. Fulltext Maternal Dexamethasone Exposure Alters Synaptic Inputs to Gonadotropin-Releasing Hormone Neurons in the Early Postnatal Rat
    Lim WL, Idris MM, Kevin FS, Soga T, Parhar IS
    Front Endocrinol (Lausanne), 2016;7:117.
    PMID: 27630615 DOI: 10.3389/fendo.2016.00117
    Maternal dexamethasone [(DEX); a glucocorticoid receptor agonist] exposure delays pubertal onset and alters reproductive behavior in the adult offspring. However, little is known whether maternal DEX exposure affects the offspring's reproductive function by disrupting the gonadotropin-releasing hormone (GnRH) neuronal function in the brain. Therefore, this study determined the exposure of maternal DEX on the GnRH neuronal spine development and synaptic cluster inputs to GnRH neurons using transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of GnRH promoter. Pregnant females were administered with DEX (0.1 mg/kg) or vehicle (VEH, water) daily during gestation day 13-20. Confocal imaging was used to examine the spine density of EGFP-GnRH neurons by three-dimensional rendering and synaptic cluster inputs to EGFP-GnRH neurons by synapsin I immunohistochemistry on postnatal day 0 (P0) males. The spine morphology and number on GnRH neurons did not change between the P0 males following maternal DEX and VEH treatment. The number of synaptic clusters within the organum vasculosum of the lamina terminalis (OVLT) was decreased by maternal DEX exposure in P0 males. Furthermore, the number and levels of synaptic cluster inputs in close apposition with GnRH neurons was decreased following maternal DEX exposure in the OVLT region of P0 males. In addition, the postsynaptic marker molecule, postsynaptic density 95, was observed in GnRH neurons following both DEX and VEH treatment. These results suggest that maternal DEX exposure alters neural afferent inputs to GnRH neurons during early postnatal stage, which could lead to reproductive dysfunction during adulthood.
  20. Fulltext Maternal dexamethasone exposure during pregnancy in rats disrupts gonadotropin-releasing hormone neuronal development in the offspring
    Lim WL, Soga T, Parhar IS
    Cell Tissue Res, 2014 Feb;355(2):409-23.
    PMID: 24374911 DOI: 10.1007/s00441-013-1765-9
    The migration of gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode to the preoptic area (POA) from embryonic day 13 is important for successful reproduction during adulthood. Whether maternal glucocorticoid exposure alters GnRH neuronal morphology and number in the offspring is unknown. This study determines the effect of maternal dexamethasone (DEX) exposure on enhanced green fluorescent protein (EGFP) driven by GnRH promoter neurons (TG-GnRH) in transgenic rats dual-labelled with GnRH immunofluorescence (IF-GnRH). The TG-GnRH neurons were examined in intact male and female rats at different postnatal ages, as a marker for GnRH promoter activity. Pregnant females were subcutaneously injected with DEX (0.1 mg/kg) or vehicle daily during gestation days 13-20 to examine the number of GnRH neurons in P0 male offspring. The total number of TG-GnRH neurons and TG-GnRH/IF-GnRH neuronal ratio increased from P0 and P5 stages to P47-52 stages, suggesting temporal regulation of GnRH promoter activity during postnatal development in intact rats. In DEX-treated P0 males, the number of IF-GnRH neurons decreased within the medial septum, organum vasculosom of the lamina terminalis (OVLT) and anterior hypothalamus. The percentage of TG-GnRH neurons with branched dendritic structures decreased in the OVLT of DEX-P0 males. These results suggest that maternal DEX exposure affects the number and dendritic development of early postnatal GnRH neurons in the OVLT/POA, which may lead to altered reproductive functions in adults.
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