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1 H-NMR metabolomics for evaluating the protective effect of Clinacanthus nutans (Burm. f) Lindau water extract against nitric oxide production in LPS-IFN-γ activated RAW 264.7 macrophages

Khoo LW, Kow ASF, Maulidiani M, Ang MY, Chew WY, Lee MT, et al.

Phytochem Anal, 2019 Jan;30(1):46-61.
PMID: 30183131 DOI: 10.1002/pca.2789

INTRODUCTION: Clinacanthus nutans, a small shrub that is native to Southeast Asia, is commonly used in traditional herbal medicine and as a food source. Its anti-inflammation properties is influenced by the metabolites composition, which can be determined by different binary extraction solvent ratio and extraction methods used during plant post-harvesting stage.
OBJECTIVE: Evaluate the relationship between the chemical composition of C. nutans and its anti-inflammatory properties using nuclear magnetic resonance (NMR) metabolomics approach.
METHODOLOGY: The anti-inflammatory effect of C. nutans air-dried leaves extracted using five different binary extraction solvent ratio and two extraction methods was determined based on their nitric oxide (NO) inhibition effect in lipopolysaccharide-interferon-gamma (LPS-IFN-γ) activated RAW 264.7 macrophages. The relationship between extract bioactivity and metabolite profiles and quantifications were established using 1 H-NMR metabolomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The possible metabolite biosynthesis pathway was constructed to further strengthen the findings.
RESULTS: Water and sonication prepared air-dried leaves possessed the highest NO inhibition activity (IC50 = 190.43 ± 12.26 μg/mL, P
Fulltext Success stories in genomic medicine from resource-limited countries

Mitropoulos K, Al Jaibeji H, Forero DA, Laissue P, Wonkam A, Lopez-Correa C, et al.

Hum Genomics, 2015 Jun 18;9:11.
PMID: 26081768 DOI: 10.1186/s40246-015-0033-3

In recent years, the translation of genomic discoveries into mainstream medical practice and public health has gained momentum, facilitated by the advent of new technologies. However, there are often major discrepancies in the pace of implementation of genomic medicine between developed and developing/resource-limited countries. The main reason does not only lie in the limitation of resources but also in the slow pace of adoption of the new findings and the poor understanding of the potential that this new discipline offers to rationalize medical diagnosis and treatment. Here, we present and critically discuss examples from the successful implementation of genomic medicine in resource-limited countries, focusing on pharmacogenomics, genome informatics, and public health genomics, emphasizing in the latter case genomic education, stakeholder analysis, and economics in pharmacogenomics. These examples can be considered as model cases and be readily replicated for the wide implementation of pharmacogenomics and genomic medicine in other resource-limited environments.
Relationship between food habits and tooth erosion occurrence in Malaysian University students

Manaf ZA, Lee MT, Ali NH, Samynathan S, Jie YP, Ismail NH, et al.

Malays J Med Sci, 2012 Apr;19(2):56-66.
PMID: 22973138 MyJurnal

BACKGROUND: Tooth erosion is a growing dental problem; however, the role of diet in the aetiology of tooth erosion is unclear. A cross-sectional study was conducted to determine the association between tooth erosion occurrence and the consumption of acidic foods and drinks among undergraduate university students.
METHODS: A total of 150 undergraduate students (33 males and 117 females) aged 19 to 24 years at Universiti Kebangsaan Malaysia participated in this study. The Basic Erosive Wear Examination was used to assess the occurrence of tooth erosion. Information regarding dental hygiene practices, usual dietary habits, and consumption of acidic foods and drinks was obtained through a structured questionnaire.
RESULTS: In all, 68% of subjects had tooth erosion. Subjects who reported having received information about healthy eating were less likely to have tooth erosion (χ(2) [1, N = 150] = 7.328, P = 0.007). The frequencies of milk (OR = 0.29, 95% CI = 0.13-0.67) and tea/coffee (adjusted OR = 0.42, 95% CI = 0.19-0.95) consumption were negatively associated with tooth erosion. Dental hygiene practice, the frequency and amount of acidic food and drink intake, and body mass index classification were not significantly associated with the risk of tooth erosion (P > 0.05).
CONCLUSION: A high prevalence of tooth erosion was observed among this group of students. Preventive measures, such as dietary advice and increased consumption of milk at a younger age, may reduce the occurrence of tooth erosion among this age group.
Fulltext The α6 subunit-containing GABAA receptor: A novel drug target for inhibition of trigeminal activation

Fan PC, Lai TH, Hor CC, Lee MT, Huang P, Sieghart W, et al.

Neuropharmacology, 2018 09 15;140:1-13.
PMID: 30016665 DOI: 10.1016/j.neuropharm.2018.07.017

Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABAA receptors (α6GABAARs) are expressed in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS) that is involved in the pathogenesis of migraine. Here we reveal an unprecedented role of α6GABAARs in ameliorating TGVS activation using several pharmacological approaches in an animal model mimicking pathological changes in migraine. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in Wistar rats. Centrally, i.c. capsaicin activated the trigeminal cervical complex (TCC) measured by the increased number of c-Fos-immunoreactive (c-Fos-ir) TCC neurons. Peripherally, it elevated calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG and depleted CGRP-ir in the dura mater. Pharmacological approaches included a recently identified α6GABAAR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABAAR-active PAMs (Ro15-4513 and loreclezole), an α6GABAAR-inactive benzodiazepine (diazepam), an α6GABAAR-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these compounds on both central and peripheral TGVS responses induced by i.c. capsaicin. Compound 6 (3-10 mg/kg, i.p.) significantly attenuated the TCC neuronal activation and TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin. All these effects of Compound 6 were mimicked by topiramate, Ro15-4513 and loreclezole, but not by diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the α6GABAAR in TG is a novel drug target for TGVS activation and that α6GABAAR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine.
Plasma and urine metabolite profiling reveals the protective effect of Clinacanthus nutans in an ovalbumin-induced anaphylaxis model: 1H-NMR metabolomics approach

Khoo LW, Audrey Kow SF, Maulidiani M, Lee MT, Tan CP, Shaari K, et al.

J Pharm Biomed Anal, 2018 Sep 05;158:438-450.
PMID: 29957507 DOI: 10.1016/j.jpba.2018.06.038

The present study sought to identify the key biomarkers and pathways involved in the induction of allergic sensitization to ovalbumin and to elucidate the potential anti-anaphylaxis property of Clinacanthus nutans (Burm. f.) Lindau water leaf extract, a Southeast Asia herb in an in vivo ovalbumin-induced active systemic anaphylaxis model evaluated by 1H-NMR metabolomics. The results revealed that carbohydrate metabolism (glucose, myo-inositol, galactarate) and lipid metabolism (glycerol, choline, sn-glycero-3-phosphocholine) are the key requisites for the induction of anaphylaxis reaction. Sensitized rats treated with 2000 mg/kg bw C. nutans extract before ovalbumin challenge showed a positive correlation with the normal group and was negatively related to the induced group. Further 1H-NMR analysis in complement with Kyoto Encyclopedia of Genes and Genomes (KEGG) reveals the protective effect of C. nutans extract against ovalbumin-induced anaphylaxis through the down-regulation of lipid metabolism (choline, sn-glycero-3-phosphocholine), carbohydrate and signal transduction system (glucose, myo-inositol, galactarate) and up-regulation of citrate cycle intermediates (citrate, 2-oxoglutarate, succinate), propanoate metabolism (1,2-propanediol), amino acid metabolism (betaine, N,N-dimethylglycine, methylguanidine, valine) and nucleotide metabolism (malonate, allantoin). In summary, this study reports for the first time, C. nutans water extract is a potential anti-anaphylactic agent and 1H-NMR metabolomics is a great alternative analytical tool to explicate the mechanism of action of anaphylaxis.
Fulltext Hematological, Biochemical, Histopathological and ¹H-NMR Metabolomics Application in Acute Toxicity Evaluation of Clinacanthus nutans Water Leaf Extract

Khoo LW, Foong Kow AS, Maulidiani M, Lee MT, Tan CP, Shaari K, et al.

Molecules, 2018 Aug 29;23(9).
PMID: 30158427 DOI: 10.3390/molecules23092172

The present study aims for the first time to provide the in vivo acute toxicological profile of the highest dose of Clinacanthus nutans (Burm. f.) Lindau water leaf extract according to the Organization for economic co-operation and development (OECD) 423 guidelines through conventional toxicity and advanced proton nuclear magnetic resonance (¹H-NMR) serum and urinary metabolomics evaluation methods. A single dose of 5000 mg/kg bw of C. nutans water extract was administered to Sprague Dawley rats, and they were observed for 14 days. Conventional toxicity evaluation methods (physical observation, body and organ weight, food and water consumption, hematology, biochemical testing and histopathological analysis) suggested no abnormal toxicity signs. Serum ¹H-NMR metabolome revealed no significant metabolic difference between untreated and treated groups. Urinary ¹H-NMR analysis, on the other hand, revealed alteration in carbohydrate metabolism, energy metabolism and amino acid metabolism in extract-treated rats after 2 h of extract administration, but the metabolic expression collected after 24 h and at Day 5, Day 10 and Day 15 indicated that the extract-treated rats did not accumulate any toxicity biomarkers. Importantly, the outcomes further suggest that single oral administration of up to 5000 mg/kg bw of C. nutans water leaf extract is safe for consumption.
Fulltext Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia

Lee MT, Chiu YT, Chiu YC, Hor CC, Lee HJ, Guerrini R, et al.

J Biomed Sci, 2020 Jan 09;27(1):7.
PMID: 31915019 DOI: 10.1186/s12929-019-0590-1

BACKGROUND: Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model.
METHODS: Male C57BL/6 mice of 8-12 week-old were subjected to intra-cerebroventricular (i.c.v.) and/or intra-vlPAG (i.pag.) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice.
RESULTS: NPS (i.c.v., but not i.pag.) induced antinociception. This effect was prevented by i.c.v. blockade of NPSRs. Substance P (i.pag.) and orexin-A (i.pag.) also induced antinociception. Substance P (i.pag.)-induced antinociception was prevented by i.pag. Blockade of NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice.
CONCLUSIONS: These results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.
Rapid antidepressant-like effects of muscarinic receptor antagonists require BDNF-dependent signaling in the ventrolateral periaqueductal gray

Kan HW, Peng WH, Wu CC, Wang DW, Lee MT, Lee YK, et al.

Psychopharmacology (Berl), 2022 Dec;239(12):3805-3818.
PMID: 36221037 DOI: 10.1007/s00213-022-06250-1

RATIONALE: Clinical reports reveal that scopolamine, an acetylcholine muscarinic receptor antagonist, exerts rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic effects have not been fully identified.
OBJECTIVES: The present study examines the cellular mechanisms by which scopolamine produces antidepressant-like effects through its action in the ventrolateral midbrain periaqueductal gray (vlPAG).
METHODS: We used a well-established mouse model of depression induced by chronic restraint stress (CRS) exposure for 14 days. Behaviors were tested using the forced swim test (FST), tail suspension test (TST), female urine sniffing test (FUST), novelty-suppressed feeding test (NSFT), and locomotor activity (LMA). Synaptic transmission in the vlPAG was measured by whole-cell patch-clamp recordings. IntravlPAG microinjection was used to pharmacologically verify the signaling cascades of scopolamine in the vlPAG.
RESULTS: The results demonstrated that intraperitoneal injection of scopolamine produced antidepressant-like effects in a dose-dependent manner without affecting locomotor activity. CRS elicited depression-like behaviors, whereas intraperitoneal injection of scopolamine alleviated CRS-induced depression-like behaviors. CRS diminished glutamatergic transmission in the vlPAG, while scopolamine reversed the above effects. Moreover, intravlPAG microinjection of the L-type voltage-dependent calcium channel (VDCC) blocker verapamil, tropomyosin-related kinase B (TrkB) receptor antagonist ANA-12, mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist CNQX prevented scopolamine-induced antidepressant-like effects.
CONCLUSIONS: Scopolamine ameliorated CRS-elicited depression-like behavior required activation of VDCC, resulting in activity-dependent release of brain-derived neurotrophic factor (BDNF), engaging the TrkB receptor and downstream mTORC1 signaling in the vlPAG.
Clinacanthus nutans aqueous leaves extract exerts anti-allergic activity in preclinical anaphylactic models via alternative IgG pathway

Kow ASF, Khoo LW, Tan JW, Abas F, Lee MT, Israf DA, et al.

J Ethnopharmacol, 2023 Mar 01;303:116003.
PMID: 36464074 DOI: 10.1016/j.jep.2022.116003

ETHNOPHARMACOLOGICAL RELEVANCE: Allergy is mediated by the crosslinking of immunoglobulins (Ig) -E or -G to their respective receptors, which degranulates mast cells, macrophages, basophils, or neutrophils, releasing allergy-causing mediators. The removal of these mediators such as histamine, platelet-activating factor (PAF) and interleukins (ILs) released by effector cells will alleviate allergy. Clinacanthus nutans (C. nutans), an herbal plant in Southeast Asia, is used traditionally to treat skin rash, an allergic symptom. Previously, we have reported that C. nutans aqueous leaves extract (CNAE) was able to suppress the release of β-hexosaminidase and histamine but not interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-α) in the IgE-induced mast cell degranulation model at 5 mg/mL and above. We also found that CNAE could protect rats against ovalbumin-challenged active systemic anaphylaxis (OVA-ASA) through the downregulation and upregulation of certain metabolites using proton nuclear magnetic resonance (1H-NMR) metabolomics approach.
AIM OF THE STUDY: As allergy could be mediated by both IgE and IgG, we further evaluated the anti-allergy potential of CNAE in both in vitro model of IgG-induced macrophage activation and in vivo anaphylaxis models to further dissect the mechanism of action underlying the anti-allergic properties of CNAE.
MATERIAL & METHODS: The anti-allergy potential of CNAE was evaluated in in vivo anaphylaxis models of ovalbumin-challenged active systemic anaphylaxis (OVA-ASA) and IgE-challenged passive systemic anaphylaxis (PSA) using Sprague Dawley rats as well as IgG-challenged passive systemic anaphylaxis (IgG-PSA) using C57BL/6 mice. Meanwhile, in vitro model of IgG-induced macrophage activation model was performed using IC-21 macrophages. The release of soluble mediators from both IgE and IgG-mediated pathways were measured using enzyme-linked immunosorbent assay (ELISA). The signaling molecules targeted by CNAE were identified by performing Western blot.
RESULTS: IgG, platelet-activating factor (PAF) and IL-6 was suppressed by CNAE in OVA-ASA, but not IgE. In addition, CNAE significantly suppressed PAF and IL-6 in IgG-PSA but did not suppress histamine, IL-4 and leukotrienes C4 (LTC4) in IgE-PSA. CNAE also inhibited IL-6 and TNF-α by inhibiting the phosphorylation of ERK1/2 in the IgG-induced macrophage activation model.
CONCLUSION: Overall, our findings supported that CNAE exerts its anti-allergic properties by suppressing the IgG pathway and its mediators by inhibiting ERK1/2 phosphorylation, thus providing scientific evidence supporting its traditional use in managing allergy.
Fulltext Cerebellar α6GABAA Receptors as a Therapeutic Target for Essential Tremor: Proof-of-Concept Study with Ethanol and Pyrazoloquinolinones

Huang YH, Lee MT, Hsueh HY, Knutson DE, Cook J, Mihovilovic MD, et al.

Neurotherapeutics, 2023 Mar;20(2):399-418.
PMID: 36696034 DOI: 10.1007/s13311-023-01342-y

Ethanol has been shown to suppress essential tremor (ET) in patients at low-to-moderate doses, but its mechanism(s) of action remain unknown. One of the ET hypotheses attributes the ET tremorgenesis to the over-activated firing of inferior olivary neurons, causing synchronic rhythmic firings of cerebellar Purkinje cells. Purkinje cells, however, also receive excitatory inputs from granule cells where the α6 subunit-containing GABAA receptors (α6GABAARs) are abundantly expressed. Since ethanol is a positive allosteric modulator (PAM) of α6GABAARs, such action may mediate its anti-tremor effect. Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of ethanol and α6GABAAR-selective pyrazoloquinolinone PAMs. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Ethanol significantly and dose-dependently attenuated action tremor at non-sedative doses (0.4-2.4 g/kg, i.p.). Propranolol and α6GABAAR-selective pyrazoloquinolinones also significantly suppressed tremor activity. Neither ethanol nor propranolol, but only pyrazoloquinolinones, restored burrowing activity in harmaline-treated mice. Importantly, intra-cerebellar micro-injection of furosemide (an α6GABAAR antagonist) had a trend of blocking the effect of pyrazoloquinolinone Compound 6 or ethanol on harmaline-induced tremor. In addition, the anti-tremor effects of Compound 6 and ethanol were synergistic. These results suggest that low doses of ethanol and α6GABAAR-selective PAMs can attenuate action tremor, at least partially by modulating cerebellar α6GABAARs. Thus, α6GABAARs are potential therapeutic targets for ET, and α6GABAAR-selective PAMs may be a potential mono- or add-on therapy.
Fulltext α6GABAA Receptor Positive Modulators Alleviate Migraine-like Grimaces in Mice via Compensating GABAergic Deficits in Trigeminal Ganglia

Tzeng HR, Lee MT, Fan PC, Knutson DE, Lai TH, Sieghart W, et al.

Neurotherapeutics, 2021 Jan;18(1):569-585.
PMID: 33111258 DOI: 10.1007/s13311-020-00951-1

Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABAA receptors (α6GABAARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAAR expression in NTG-treated mice, we demonstrated that an α6GABAAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABAARs in TG are potential targets for migraine treatment. Thus, α6GABAAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.
Fulltext Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray

Chen YH, Lee HJ, Lee MT, Wu YT, Lee YH, Hwang LL, et al.

Proc Natl Acad Sci U S A, 2018 11 06;115(45):E10720-E10729.
PMID: 30348772 DOI: 10.1073/pnas.1807991115

Adequate pain management remains an unmet medical need. We previously revealed an opioid-independent analgesic mechanism mediated by orexin 1 receptor (OX1R)-initiated 2-arachidonoylglycerol (2-AG) signaling in the ventrolateral periaqueductal gray (vlPAG). Here, we found that low-frequency median nerve stimulation (MNS) through acupuncture needles at the PC6 (Neiguan) acupoint (MNS-PC6) induced an antinociceptive effect that engaged this mechanism. In mice, MNS-PC6 reduced acute thermal nociceptive responses and neuropathy-induced mechanical allodynia, increased the number of c-Fos-immunoreactive hypothalamic orexin neurons, and led to higher orexin A and lower GABA levels in the vlPAG. Such responses were not seen in mice with PC6 needle insertion only or electrical stimulation of the lateral deltoid, a nonmedian nerve-innervated location. Directly stimulating the surgically exposed median nerve also increased vlPAG orexin A levels. MNS-PC6-induced antinociception (MNS-PC6-IA) was prevented by proximal block of the median nerve with lidocaine as well as by systemic or intravlPAG injection of an antagonist of OX1Rs or cannabinoid 1 receptors (CB1Rs) but not by opioid receptor antagonists. Systemic blockade of OX1Rs or CB1Rs also restored vlPAG GABA levels after MNS-PC6. A cannabinoid (2-AG)-dependent mechanism was also implicated by the observations that MNS-PC6-IA was prevented by intravlPAG inhibition of 2-AG synthesis and was attenuated in Cnr1-/- mice. These findings suggest that PC6-targeting low-frequency MNS activates hypothalamic orexin neurons, releasing orexins to induce analgesia through a CB1R-dependent cascade mediated by OX1R-initiated 2-AG retrograde disinhibition in the vlPAG. The opioid-independent characteristic of MNS-PC6-induced analgesia may provide a strategy for pain management in opioid-tolerant patients.
Stress induces reinstatement of extinguished cocaine conditioned place preference by a sequential signaling via neuropeptide S, orexin, and endocannabinoid

Chou YH, Hor CC, Lee MT, Lee HJ, Guerrini R, Calo G, et al.

Addict Biol, 2020 Oct 19.
PMID: 33078457 DOI: 10.1111/adb.12971

Neurons containing neuropeptide S (NPS) and orexins are activated during stress. Previously, we reported that orexins released during stress, via orexin OX1 receptors (OX1 Rs), contribute to the reinstatement of cocaine seeking through endocannabinoid/CB1 receptor (CB1 R)-mediated dopaminergic disinhibition in the ventral tegmental area (VTA). Here, we further demonstrated that NPS released during stress is an up-stream activator of this orexin-endocannabinoid cascade in the VTA, leading to the reinstatement of cocaine seeking. Mice were trained to acquire cocaine conditioned place preference (CPP) by context-pairing cocaine injections followed by the extinction training with context-pairing saline injections. Interestingly, the extinguished cocaine CPP in mice was significantly reinstated by intracerebroventricular injection (i.c.v.) of NPS (1 nmol) in a manner prevented by intraperitoneal injection (i.p.) of SHA68 (50 mg/kg), an NPS receptor antagonist. This NPS-induced cocaine reinstatement was prevented by either i.p. or intra-VTA microinjection (i.vta.) of SB-334867 (15 mg/kg, i.p. or 15 nmol, i.vta.) and AM 251 (1.1 mg/kg, i.p. or 30 nmol, i.vta.), antagonists of OX1 Rs and CB1 Rs, respectively. Besides, NPS (1 nmol, i.c.v.) increased the number of c-Fos-containing orexin neurons in the lateral hypothalamus (LH) and increased orexin-A level in the VTA. The latter effect was blocked by SHA68. Furthermore, a 30-min restraint stress in mice reinstated extinguished cocaine CPP and was prevented by SHA68. These results suggest that NPS is released upon stress and subsequently activates LH orexin neurons to release orexins in the VTA. The released orexins then reinstate extinguished cocaine CPP via an OX1 R- and endocannabinoid-CB1 R-mediated signaling in the VTA.
Fulltext Age-Dependent Anti-migraine Effects of Valproic Acid and Topiramate in Rats

Huang P, Kuo PH, Lee MT, Chiou LC, Fan PC

Front Pharmacol, 2018;9:1095.
PMID: 30319425 DOI: 10.3389/fphar.2018.01095

Background: Valproic acid (VPA) and topiramate (TPM), initially developed as antiepileptics, are approved for migraine prophylaxis in adults but not children. The differences in their antimigraine mechanism(s) by age remain unclear. Methods: A migraine model induced by intra-cisternal (i.c.) capsaicin instillation in pediatric (4-5 weeks) and adult (8-9 weeks) rats was pretreated with VPA (30, 100 mg/kg) or TPM (10, 30, 100 mg/kg). Noxious meningeal stimulation by the irritant capsaicin triggered trigeminovascular system (TGVS) activation mimicking migraine condition, which were assessed peripherally by the depletion of calcitonin gene-related peptide (CGRP) in sensory nerve fibers of the dura mater, the increased CGRP immunoreactivity at trigeminal ganglia (TG) and centrally by the number of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminocervical complex (TCC). Peripherally, CGRP released from dural sensory nerve terminals of TG triggered pain signal transmission in the primary afferent of trigeminal nerve, which in turn caused central sensitization of the TGVS due to TCC activation and hence contributed to migraine. Results: In the VPA-treated group, the central responsiveness expressed by reducing the number of c-Fos-ir neurons, which had been increased by i.c. capsaicin, was significant in pediatric, but not adult, rats. Inversely, VPA was effective in peripheral inhibition of elevated CGRP immunoreactivity in the TG and CGRP depletion in the dura mater of adult, but not pediatric, rats. In TPM group, the central responsiveness was significant in both adult and pediatric groups. Peripherally, TPM significantly inhibited capsaicin-induced CGRP expression of TG in adult, but not pediatric, rats. Interestingly, the capsaicin-induced depletion of CGRP in dura was significantly rescued by TPM at high doses in adults, but at low dose in pediatric group. Conclusion: These results suggest VPA exerted peripheral inhibition in adult, but central suppression in pediatric migraine-rats. In contrast, TPM involves both central and peripheral inhibition of migraine with an optimal therapeutic window in both ages. These findings may clarify the age-dependent anti-migraine mechanism of VPA and TPM, which may guide the development of new pediatric anti-migraine drugs in the future.
Fulltext Plasma calcitonin gene-related peptide: A potential biomarker for diagnosis and therapeutic responses in pediatric migraine

Fan PC, Kuo PH, Lee MT, Chang SH, Chiou LC

Front Neurol, 2019;10:10.
PMID: 30733702 DOI: 10.3389/fneur.2019.00010

Background: Plasma calcitonin gene-related peptide (CGRP) plays a key role in the migraine pathophysiology. This study aimed to investigate its role in predicting diagnosis and outcome of pharmacotherapy in pediatric migraine. Methods: We prospectively recruited 120 subjects, who never took migraine-preventive agents in a pediatric clinic, including 68 patients with migraine, 30 with non-migraine headache (NM), and 22 non-headache (NH) age-matched controls. Short-term therapeutic response was measured for at least 2 weeks after the start of therapy. Responders were defined with >50% headache reduction. Plasma CGRP concentrations were measured by ELISA. Results: In the migraine group, more patients required acute therapy, as compared to the NM group (62/68, 91% vs. 5/30, 15%, p = 0.001). The mean plasma CGRP level in migraineurs either during (291 ± 60 pg/ml) or between (240 ± 48) attacks was higher than in NM patients (51 ± 5 pg/ml, p = 0.006 and 0.018, respectively) and NH controls (53 ± 6 pg/ml, p = 0.016 and 0.045, respectively). Forty-seven patients (69%) needed preventive treatments and had higher plasma CGRP levels (364 ± 62 pg/ml, n = 47) than those not (183 ± 54 pg/ml, n = 21) (p = 0.031). Topiramate responders had higher plasma CGRP levels than non-responders (437 ± 131 pg/ml, n = 14 vs. 67 ± 19 pg/ml, n = 6, p = 0.021). Survival curves of plasma CGRP levels also showed those with higher CGRP levels responded better to topiramate. Differences were not found in the other preventives. Conclusion: The plasma CGRP level can differentiate migraine from non-migraine headache. It may also serve as a reference for the therapeutic strategy since it is higher in patients requiring migraine prevention and responsive to short-term topiramate treatment. These results are clinically significant, especially for the young children who cannot clearly describe their headache symptoms and may provide new insights into the clinical practice for the diagnosis and treatment of pediatric migraine.
Study site: Paediatric outpatient clinic,National Taiwan University Hospital (NTUH), Taiwan
Fulltext Sensitization effect of kaempferol from persimmon leaves on HepG2 hepatoma cells with ABT-199 resistance and its molecular mechanisms

Chen L, Jiang X, Gao S, Liu X, Gao Y, Kow ASF, et al.

Front Pharmacol, 2022;13:1032069.
PMID: 36386146 DOI: 10.3389/fphar.2022.1032069

ABT-199 (venetoclax) is the first-in-class selective B-cell lymphoma 2 (BCL2) inhibitor, which is known to be ineffective towards liver cancer cells. Here, we investigated the efficacy and the underlying molecular processes of the sensitization effect of kaempferol isolated from persimmon leaves (KPL) on the ABT-199-resistant HepG2 cells. The effects of various doses of KPL coupled with ABT-199 on the proliferation of HepG2 cells and on the H22 liver tumor-bearing mouse model were examined, as well as the underlying mechanisms. Our findings showed that ABT-199 alone, in contrast to KPL, had no significant impact on hepatoma cell growth, both in vitro and in vivo. Interestingly, the combination therapy showed significantly higher anti-hepatoma efficacy. Mechanistic studies revealed that combining KPL and ABT-199 may promote both early and late apoptosis, as well as decrease the mitochondrial membrane potential in HepG2 cells. Western blot analysis showed that combination of KPL and ABT-199 significantly reduced the expression of the anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, raised the expression of Bax and cleaved caspase 3, and enhanced cytochrome C release and Bax translocation. Therefore, KPL combined with ABT-199 has a potential application prospect in the treatment of hepatocellular carcinoma.
Fulltext Ameliorative Effect of Tocotrienols on Perimenopausal-Associated Osteoporosis-A Review

Liang G, Kow ASF, Tham CL, Ho YC, Lee MT

Antioxidants (Basel), 2022 Nov 03;11(11).
PMID: 36358550 DOI: 10.3390/antiox11112179

Osteoporosis, or bone loss, is a disease that affects many women globally. As life expectancy increases, the risk of osteoporosis in women also increases, too, and this will create a burden on the healthcare and economic sectors of a country. Osteoporosis was once thought to be a disease that would occur only after menopause. However, many studies have shown that osteoporosis may develop even in the perimenopausal stage. Due to the erratic levels of estrogen and progesterone during the perimenopausal stage, studies suggest that women are exposed to the risk of developing osteoporosis even at this stage. The erratic hormonal changes result in the production of proinflammatory mediators and cause oxidative stress, which leads to the progressive loss of bone-building activities. Tocotrienols, members of vitamin E, have many health-promoting properties. Due to their powerful anti-oxidative and anti-inflammatory properties, tocotrienols have shown positive anti-osteoporotic properties in post-menopausal studies. Hence, we propose here that tocotrienols could also possibly alleviate perimenopausal osteoporosis by discussing in this review the connection between inflammatory mediators produced during perimenopause and the risk of osteoporosis. Tocotrienols could potentially be an anti-osteoporotic agent, but due to their low bioavailability, they have not been as effective as they could be. Several approaches have been evaluated to overcome this issue, as presented in this review. As the anti-osteoporotic effects of tocotrienols were mostly studied in post-menopausal models, we hope that this review could pave the way for more research to be done to evaluate their effect on peri-menopausal models so as to reduce the risk of osteoporosis from an earlier stage.
Fulltext Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia

Al-Nema M, Gaurav A, Lee MT, Okechukwu P, Nimmanpipug P, Lee VS

PLoS One, 2022;17(12):e0278216.
PMID: 36454774 DOI: 10.1371/journal.pone.0278216

Phosphodiesterase 1B (PDE1B) and PDE10A are dual-specificity PDEs that hydrolyse both cyclic adenosine monophosphate and cyclic guanosine monophosphate, and are highly expressed in the striatum. Several reports have suggested that PDE10A inhibitors may present a promising approach for the treatment of positive symptoms of schizophrenia, whereas PDE1B inhibitors may present a novel mechanism to modulate cognitive deficits. Previously, we have reported a novel dual inhibitor of PDE1B and PDE10A, compound 2 [(3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone] which has shown inhibitory activity for human recombinant PDE1B and PDE10A in vitro. In the present study, the safety profile of compound 2 has been evaluated in rats in the acute oral toxicity study, as well as; the antipsychotic-like effects in the rat model of schizophrenia. Compound 2 was tolerated up to 1 g/kg when administered at a single oral dose. Additionally, compound 2 has strongly suppressed ketamine-induced hyperlocomotion, which presented a model for the positive symptoms of schizophrenia. It has also shown an ability to attenuate social isolation induced by chronic administration of ketamine and enhanced recognition memory of rats in the novel object recognition test. Altogether, our results suggest that compound 2 represents a promising therapy for the treatment of the three symptomatic domains of schizophrenia.
Fulltext Alcohol Withdrawal and the Associated Mood Disorders-A Review

Ngui HHL, Kow ASF, Lai S, Tham CL, Ho YC, Lee MT

Int J Mol Sci, 2022 Nov 29;23(23).
PMID: 36499240 DOI: 10.3390/ijms232314912

Recreational use of alcohol is a social norm in many communities worldwide. Alcohol use in moderation brings pleasure and may protect the cardiovascular system. However, excessive alcohol consumption or alcohol abuse are detrimental to one's health. Three million deaths due to excessive alcohol consumption were reported by the World Health Organization. Emerging evidence also revealed the danger of moderate consumption, which includes the increased risk to cancer. Alcohol abuse and periods of withdrawal have been linked to depression and anxiety. Here, we present the effects of alcohol consumption (acute and chronic) on important brain structures-the frontal lobe, the temporal lobe, the limbic system, and the cerebellum. Apart from this, we also present the link between alcohol abuse and withdrawal and mood disorders in this review, thus drawing a link to oxidative stress. In addition, we also discuss the positive impacts of some pharmacotherapies used. Due to the ever-rising demands of life, the cycle between alcohol abuse, withdrawal, and mood disorders may be a never-ending cycle of destruction. Hence, through this review, we hope that we can emphasise the importance and urgency of managing this issue with the appropriate approaches.
Fulltext Interferon therapy and its association with depressive disorders - A review

Lai JY, Ho JX, Kow ASF, Liang G, Tham CL, Ho YC, et al.

Front Immunol, 2023;14:1048592.
PMID: 36911685 DOI: 10.3389/fimmu.2023.1048592

Interferons (IFNs) are important in controlling the innate immune response to viral infections. Besides that, studies have found that IFNs also have antimicrobial, antiproliferative/antitumor and immunomodulatory effects. IFNs are divided into Type I, II and III. Type I IFNs, in particular IFN-α, is an approved treatment for hepatitis C. However, patients developed neuropsychological disorders during treatment. IFN-α induces proinflammatory cytokines, indoleamine 2,3-dioxygenase (IDO), oxidative and nitrative stress that intensifies the body's inflammatory response in the treatment of chronic inflammatory disease. The severity of the immune response is related to behavioral changes in both animal models and humans. Reactive oxygen species (ROS) is important for synaptic plasticity and long-term potentiation (LTP) in the hippocampus. However, excess ROS will generate highly reactive free radicals which may lead to neuronal damage and neurodegeneration. The limbic system regulates memory and emotional response, damage of neurons in this region is correlated with mood disorders. Due to the drawbacks of the treatment, often patients will not complete the treatment sessions, and this affects their recovery process. However, with proper management, this could be avoided. This review briefly describes the different types of IFNs and its pharmacological and clinical usages and a focus on IFN-α and its implications on depression.

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