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Ketamine Metabolites-waiting in the Wings as Therapeutic Candidate for Depression?

Lee MT, Ho YC

Curr Mol Pharmacol, 2024;17:e080823219541.
PMID: 37553766 DOI: 10.2174/1874467217666230808162402
Orexin-mediated restoration of hippocampal synaptic potentiation in mice with established cocaine-conditioned place preference

Lu GL, Lee MT, Chiou LC

Addict Biol, 2019 11;24(6):1153-1166.
PMID: 30276922 DOI: 10.1111/adb.12672

Orexins (also called hypocretins) are implicated in reward and addiction, but little is known about their role(s) in the association between hippocampal synaptic plasticity and drug preference. Previously, we found that exogenous orexin via OX1 and OX2 receptors can impair low frequency stimulation-induced depotentiation, i.e. restoring potentiation of excitatory synaptic transmission (re-potentiation) in mouse hippocampal slices. Here, we found this re-potentiation in hippocampal slices from mice that had acquired conditioned place preference (CPP) to cocaine. Both 10 and 20 mg/kg of cocaine induced similar magnitudes of CPP in mice and re-potentiation in their hippocampal slices, but differed in their susceptibility to TCS1102, a dual (OX1 and OX2 ) orexin receptor antagonist. TCS1102 significantly attenuated CPP and hippocampal re-potentiation induced by cocaine at 10 mg/kg but not at 20 mg/kg. Nonetheless, SCH23390, an antagonist of dopamine D1-like receptors (D1-likeRs), inhibited the effects induced by both doses of cocaine. SKF38393, a D1-likeR-selective agonist, also induced hippocampal re-potentiation in vitro. Interestingly, this effect was attenuated by TCS1102. Conversely, SCH23390 prevented orexin A-induced hippocampal re-potentiation. These results suggest that endogenous orexins are released in mice during cocaine-CPP acquisition, which sustains potentiated hippocampal transmission via OX1 /OX2 receptors and may contribute to the addiction memory of cocaine. This effect of endogenous orexins, however, may be substituted by dopamine that may dominate hippocampal re-potentiation and CPP via D1-likeRs when the reinforcing effect of cocaine is high.
Fulltext Alternative pain management via endocannabinoids in the time of the opioid epidemic: Peripheral neuromodulation and pharmacological interventions

Lee MT, Mackie K, Chiou LC

Br J Pharmacol, 2023 Apr;180(7):894-909.
PMID: 34877650 DOI: 10.1111/bph.15771

The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the endocannabinoid system in the CNS, via activation of CB1 receptors in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB1 receptors in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB1 receptor agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered positive allosteric modulators of CB1 receptors. On the other hand, as non-pharmacological pain relief is advocated by the US-NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation-induced analgesia is also discussed. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.
Median Nerve Stimulation as a Nonpharmacological Approach to Bypass Analgesic Tolerance to Morphine: A Proof-of-Concept Study in Mice

Lee MT, Chen YH, Mackie K, Chiou LC

J Pain, 2021 03;22(3):300-312.
PMID: 33069869 DOI: 10.1016/j.jpain.2020.09.003

Analgesic tolerance to opioids contributes to the opioid crisis by increasing the quantity of opioids prescribed and consumed. Thus, there is a need to develop non-opioid-based pain-relieving regimens as well as strategies to circumvent opioid tolerance. Previously, we revealed a non-opioid analgesic mechanism induced by median nerve electrostimulation at the overlaying PC6 (Neiguan) acupoint (MNS-PC6). Here, we further examined the efficacy of MNS-PC6 in morphine-tolerant mice with neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Daily treatments of MNS-PC6 (2 Hz, 2 mA), but not electrostimulation at a nonmedian nerve-innervated location, for a week post-CCI induction significantly suppressed established mechanical allodynia in CCI-mice in an orexin-1 (OX1) and cannabinoid-1 (CB1) receptor-dependent fashion. This antiallodynic effect induced by repeated MNS-PC6 was comparable to that induced by repeated gabapentin (50 mg/kg, i.p.) or single morphine (10 mg/kg, i.p.) treatments, but without tolerance, unlike repeated morphine-induced analgesia. Furthermore, single and repeated MNS-PC6 treatments remained fully effective in morphine-tolerant CCI-mice, also in an OX1 and CB1 receptor-dependent fashion. In CCI-mice receiving escalating doses of morphine for 21 days (10, 20 and 50 mg/kg), single and repeated MNS-PC6 treatments remained fully effective. Therefore, repeated MNS-PC6 treatments induce analgesia without tolerance, and retain efficacy in opioid-tolerant mice via a mechanism that involves OX1 and CB1 receptors. This study suggests that MNS-PC6 is an alternative pain management strategy that maybe useful for combatting the opioid epidemic, and opioid-tolerant patients receiving palliative care. PERSPECTIVE: Median nerve stimulation relieves neuropathic pain in mice without tolerance and retains efficacy even in mice with analgesic tolerance to escalating doses of morphine, via an opioid-independent, orexin-endocannabinoid-mediated mechanism. This study provides a proof of concept for utilizing peripheral nerve stimulating devices 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.
Pivotal Role of Slitrk1 in Adult Striatal Cholinergic Neurons in Mice: Implication in Tourette Syndrome

Du JC, Chang MH, Yeh CJ, Lee MT, Lee HJ, Chuang SH, et al.

Ann Neurol, 2023 Sep 30.
PMID: 37776102 DOI: 10.1002/ana.26805

OBJECTIVE: The SLIT and NTRK-like 1 (SLITRK1) gene mutation and striatal cholinergic interneurons (ChIs) loss are associated with Tourette syndrome (TS). ChIs comprise only 1 to 2% of striatal neurons but project widely throughout the stratum to impact various striatal neurotransmission, including TS-related dopaminergic transmission. Here, we link striatal Slitrk1, ChI function, and dopaminergic transmission and their associations with TS-like tic behaviors.
METHODS: Slitrk1-KD mice were induced by bilaterally injecting Slitrk1 siRNA into their dorsal striatum. Control mice received scrambled siRNA injection. Their TS-like tic behaviors, prepulse inhibition, sensory-motor function and dopamine-related behaviors were compared. We also compared dopamine and ACh levels in microdialysates, Slitrk protein and dopamine transporter levels, and numbers of Slitrk-positive ChIs and activated ChIs in the striatum between two mouse groups, and electrophysiological properties between Slitrk-positive and Slitrk-negative striatal ChIs.
RESULTS: Slitrk1-KD mice exhibit TS-like haloperidol-sensitive stereotypic tic behaviors, impaired prepulse inhibition, and delayed sensorimotor response compared with the control group. These TS-like characteristics correlate with lower striatal Slitrk1 protein levels, fewer Slitrk1-containing ChIs, and fewer activated ChIs in Slitrk1-KD mice. Based on their electrophysiological properties, Slitrk1-negative ChIs are less excitable than Slitrk1-positive ChIs. Slitrk1-KD mice have lower evoked acetylcholine and dopamine levels, higher tonic dopamine levels, and downregulated dopamine transporters in the striatum, increased apomorphine-induced climbing behaviors, and impaired methamphetamine-induced hyperlocomotion compared with controls.
INTERPRETATION: Slitrk1 is pivotal in maintaining striatal ChIs activity and subsequent dopaminergic transmission for normal motor functioning. Furthermore, conditional striatal Slitrk1-KD mice may serve as a translational modality with aspects of TS phenomenology. ANN NEUROL 2023.
Impaired Ventrolateral Periaqueductal Gray-Ventral Tegmental area Pathway Contributes to Chronic Pain-Induced Depression-Like Behavior in Mice

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

Mol Neurobiol, 2023 Oct;60(10):5708-5724.
PMID: 37338803 DOI: 10.1007/s12035-023-03439-z

Chronic pain conditions within clinical populations are correlated with a high incidence of depression, and researchers have reported their high rate of comorbidity. Clinically, chronic pain worsens the prevalence of depression, and depression increases the risk of chronic pain. Individuals suffering from chronic pain and depression respond poorly to available medications, and the mechanisms underlying the comorbidity of chronic pain and depression remain unknown. We used spinal nerve ligation (SNL) in a mouse model to induce comorbid pain and depression. We combined behavioral tests, electrophysiological recordings, pharmacological manipulation, and chemogenetic approaches to investigate the neurocircuitry mechanisms of comorbid pain and depression. SNL elicited tactile hypersensitivity and depression-like behavior, accompanied by increased and decreased glutamatergic transmission in dorsal horn neurons and midbrain ventrolateral periaqueductal gray (vlPAG) neurons, respectively. Intrathecal injection of lidocaine, a sodium channel blocker, and gabapentin ameliorated SNL-induced tactile hypersensitivity and neuroplastic changes in the dorsal horn but not depression-like behavior and neuroplastic alterations in the vlPAG. Pharmacological lesion of vlPAG glutamatergic neurons induced tactile hypersensitivity and depression-like behavior. Chemogenetic activation of the vlPAG-rostral ventromedial medulla (RVM) pathway ameliorated SNL-induced tactile hypersensitivity but not SNL-elicited depression-like behavior. However, chemogenetic activation of the vlPAG-ventral tegmental area (VTA) pathway alleviated SNL-produced depression-like behavior but not SNL-induced tactile hypersensitivity. Our study demonstrated that the underlying mechanisms of comorbidity in which the vlPAG acts as a gating hub for transferring pain to depression. Tactile hypersensitivity could be attributed to dysfunction of the vlPAG-RVM pathway, while impairment of the vlPAG-VTA pathway contributed to depression-like behavior.
House dust mite allergy in Malaysia: review of research gaps in the current scenario and the way forward

Lee YZ, Kow ASF, Jacquet A, Lee MT, Tham CL

Exp Appl Acarol, 2023 Dec;91(4):509-539.
PMID: 37995026 DOI: 10.1007/s10493-023-00857-5

The prevalence of house dust mite (HDM) allergy, especially in Asian countries with rapid urbanization, has been increasing. House dust mites thrive in places with relatively high humidity. With the combination of climate change, naturally high humidity, and urbanization, tropical countries like Malaysia are becoming a hotspot for HDM allergy fast. With a previously reported sensitization rate of between 60 and 80%, it is a worrying trend for Malaysia. However, due to incomplete and out-of-date data, as seen by the limited study coverage in the past, these numbers do not paint a complete picture of the true HDM allergy scene in Malaysia. This review briefly discusses the HDM fauna, the HDM sensitization rate, the common diagnosis and therapeutic tools for HDM allergy in Malaysia, and makes suggestions for possible improvements in the future. This review also highlights the need of more comprehensive population-based prevalence studies to be done in Malaysia, encompassing the three main HDMs-Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Blomia tropicalis-as the lack of up-to-date studies failed to give a clearer picture on the current scenario of HDM allergy in Malaysia. Future studies will be beneficial to the nation in preparing a better blueprint for the management and treatment of HDM allergy.
α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials

Sieghart W, Chiou LC, Ernst M, Fabjan J, M Savić M, Lee MT

Pharmacol Rev, 2022 Jan;74(1):238-270.
PMID: 35017178 DOI: 10.1124/pharmrev.121.000293

GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6βδ GABAA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABAA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABAA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABAA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABAA receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABAA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABAA receptors. SIGNIFICANCE STATEMENT: α6-Containing GABAA receptors are abundantly expressed in cerebellar granule cells, but their pathophysiological roles are widely unknown, and they are thus out of the mainstream of GABAA receptor research. Anatomical and electrophysiological evidence indicates that these receptors have a crucial function in neuronal circuits of the cerebellum and the nervous system, and experimental, genetic, post-mortem, and pharmacological studies indicate that selective modulation of these receptors offers therapeutic prospects for a variety of neuropsychiatric disorders and for stress and its consequences.
Fulltext A Comprehensive Review on Phytochemistry and Pharmacological Activities of Clinacanthus nutans (Burm.f.) Lindau

Khoo LW, Audrey Kow S, Lee MT, Tan CP, Shaari K, Tham CL, et al.

Evid Based Complement Alternat Med, 2018;2018:9276260.
PMID: 30105077 DOI: 10.1155/2018/9276260

Clinacanthus nutans (Burm.f.) Lindau (Acanthaceae), commonly known as Sabah snake grass, is a vegetable and a well-known herb that is considered an alternative medicine for insect bites, skin rashes, herpes infection, inflammation, and cancer and for health benefits. Current review aims to provide a well-tabulated repository of the phytochemical screening, identification and quantification, and the pharmacological information of C. nutans according to the experimental design and the plant preparation methods which make it outstanding compared to existing reviews. This review has documented valuable data obtained from all accessible library databases and electronic searches. For the first time we analyzed the presence of flavonoids, triterpenoids, steroids, phytosterols, and glycosides in C. nutans based on the results from phytochemical screening which are then further confirmed by conventional phytochemical isolation methods and advanced spectroscopic techniques. Phytochemical quantification further illustrated that C. nutans is a good source of phenolics and flavonoids. Pharmacological studies on C. nutans revealed that its polar extract could be a promising anti-inflammation, antiviral, anticancer, immune and neuromodulating, and plasmid DNA protective agent; that its semipolar extract could be a promising antiviral, anticancer, and wound healing agent; and that its nonpolar extract could be an excellent anticancer agent.
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.

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