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Fulltext Role of excitatory amino acid input in rostral ventrolateral medulla neurons in rats with obesity-induced hypertension

Suhaimi FW, Yusoff NH, Dewa A, Yusof AP

Acta Neurol Belg, 2010 Mar;110(1):57-64.
PMID: 20514927

Obesity is intimately associated with hypertension; increases in blood pressure are closely related to the magnitude of weight gain. The present study aims to determine whether the excitatory amino acid input to rostral ventrolateral medulla (RVLM) contributes to elevated blood pressure in rats with diet-induced obesity. Male Sprague-Dawley rats weighing 280 to 300 grams were fed with a low-fat diet (10% kcal from fat) or moderately high-fat diet (32% kcal from fat) for 16 weeks. At week 16, rats on the moderate high-fat diet were segregated into obesity-prone and obesity-resistant rats based on body weight distribution. Baseline mean arterial pressure (MAP) was significantly higher in obesity-prone rats as compared to obesity-resistant and rats on a low-fat diet. Bilateral injection of kynurenic acid (KYN) (40 nM) into the RVLM of the obesity-prone rats reduced MAP to levels significantly different from those observed in rats on a low-fat diet and obesity-resistant rats (no change in MAP). At a lower concentration (4 nM), KYN injection did not produce any change in MAP in any group. The results obtained suggest that excitatory amino acid input to the RVLM does contribute to the development of hypertension in rats with diet-induced obesity.
Role of supraspinal vasopressin neurones in the effects of atrial natriuretic peptide on sympathetic nerve activity

Yusof AP, Yusoff NH, Suhaimi FW, Coote JH

Auton Neurosci, 2009 Jun 15;148(1-2):50-4.
PMID: 19349212 DOI: 10.1016/j.autneu.2009.03.005

The aim of the present study was to determine if paraventricular-spinal vasopressin neurones participate in the sympatho-inhibitory effects of systemically administered atrial natriuretic peptide (ANP) on renal sympathetic nerve activity (RSNA). Experiments were carried out on male Sprague-Dawley rats anesthetized with 1.3 g/kg urethane. Changes in mean arterial pressure (mm Hg), heart rate (beats per minute) and RSNA (%) were measured following intravenous bolus administration of ANP (250 ng, 500 ng and 5 microg). Intrathecal application of selective V 1a receptor antagonist was performed to test for the involvement of supraspinal vasopressin pathways in mediating the effect on sympathetic outflow evoked by intravenous ANP administration. The results obtained demonstrated that both low and high doses of ANP caused renal sympathoinhibition (250 ng; - 7.5 +/- 1%, 500 ng; - 14.2 +/- 1%, 5 microg; - 16.4 +/- 2%), concomitant with vasodilation and bradycardia. After spinal vasopressin receptor blockade, the inhibitory effects of ANP were prevented and there was a small renal sympatho-excitation (250 ng; + 1.7 +/- 0.2%, 500 ng; + 6.1 +/- 0.03%, 5 microg; + 8.0 +/- 0.03%, P < 0.05). Therefore, the renal sympathetic nerve inhibition elicited by circulating ANP is dependent on the efficacy of a well established supraspinal vasopressin pathway. Since supraspinal vasopressin neurones without exception excite renal sympathetic neurones, it is suggested that ANP elicits this effect by activating cardiac vagal afferents that inhibit the spinally projecting vasopressin neurones at their origin in the paraventricular nucleus of the hypothalamus.
The effects of chronic mitragynine (Kratom) exposure on the EEG in rats

Suhaimi FW, Hassan Z, Mansor SM, Müller CP

Neurosci Lett, 2021 02 06;745:135632.
PMID: 33444671 DOI: 10.1016/j.neulet.2021.135632

Mitragynine is the main alkaloid isolated from the leaves of Mitragyna speciosa Korth (Kratom). Kratom has been widely used to relieve pain and opioid withdrawal symptoms in humans but may also cause memory deficits. Here we investigated the changes in brain electroencephalogram (EEG) activity after acute and chronic exposure to mitragynine in freely moving rats. Vehicle, morphine (5 mg/kg) or mitragynine (1, 5 and 10 mg/kg) were administered for 28 days, and EEG activity was repeatedly recorded from the frontal cortex, neocortex and hippocampus. Repeated exposure to mitragynine increased delta, but decreased alpha powers in both cortical regions. It further decreased delta power in the hippocampus. These findings suggest that acute and chronic mitragynine can have profound effects on EEG activity, which may underlie effects on behavioral activity and cognition, particularly learning and memory function.
Mitragynine improves cognitive performance in morphine-withdrawn rats

You CY, Hassan Z, Müller CP, Suhaimi FW

Psychopharmacology (Berl), 2022 Jan;239(1):313-325.
PMID: 34693456 DOI: 10.1007/s00213-021-05996-4

RATIONALE: The treatment of opiate addiction is an unmet medical need. Repeated exposure to opiates disrupts cognitive performance. Opioid substitution therapy, with, e.g., methadone, may further exacerbate the cognitive deficits. Growing evidence suggests that mitragynine, the primary alkaloid from the Kratom (Mitragyna speciosa) leaves, may serve as a promising alternative therapy for opiate addiction. However, the knowledge of its health consequences is still limited.
OBJECTIVES: We aimed to examine the cognitive effects of mitragynine substitution in morphine-withdrawn rats. Furthermore, we asked whether neuronal addiction markers like the brain-derived neurotrophic factor (BDNF) and Ca2+/calmodulin-dependent kinase II alpha (αCaMKII) might mediate the observed effects.
METHODS: Male Sprague-Dawley rats were given morphine at escalating doses before treatment was discontinued to induce a spontaneous morphine withdrawal. Then, vehicle or mitragynine (5 mg/kg, 15 mg/kg, or 30 mg/kg) substitution was given for 3 days. A vehicle-treated group was used as a control. Withdrawal signs were scored after 24 h, 48 h, and 72 h, while novel object recognition (NOR) and attentional set-shifting (ASST) were tested during the substitution period.
RESULTS: Discontinuation of morphine significantly induced morphine withdrawal signs and cognitive deficit in the ASST. The substitution with mitragynine was able to alleviate the withdrawal signs. Mitragynine did not affect the recognition memory in the NOR but significantly improved the reversal learning deficit in the morphine-withdrawn rats.
CONCLUSIONS: These data support the idea that mitragynine could be used as safe medication therapy to treat opiate addiction with beneficial effects on cognitive deficits.
Neurobiology of Kratom and its main alkaloid mitragynine

Suhaimi FW, Yusoff NH, Hassan R, Mansor SM, Navaratnam V, Müller CP, et al.

Brain Res Bull, 2016 09;126(Pt 1):29-40.
PMID: 27018165 DOI: 10.1016/j.brainresbull.2016.03.015

Kratom or its main alkaloid, mitragynine is derived from the plant Mitragyna speciosa Korth which is indigenous to Southeast Asian countries. This substance has become widely available in other countries like Europe and United States due to its opium- and coca-like effects. In this article, we have reviewed available reports on mitragynine and other M. speciosa extracts. M. speciosa has been proven to have a rewarding effect and is effective in alleviating the morphine and ethanol withdrawal effects. However, studies in human revealed that prolonged consumption of this plant led to dependence and tolerance while cessation caused a series of aversive withdrawal symptoms. Findings also showed that M. speciosa extracts possess antinociceptive, anti-inflammatory, anti-depressant, and muscle relaxant properties. Available evidence further supports the adverse effects of M. speciosa preparations, mitragynine on cognition. Pharmacological activities are mainly mediated via opioid receptors as well as neuronal Ca2+ channels, expression of cAMP and CREB protein and via descending monoaminergic system. Physicochemical properties of mitragynine have been documented which may further explain the variation in pharmacological responses. In summary, current researchs on its main indole alkaloid, mitragynine suggest both therapeutic and addictive potential but further research on its molecular effects is needed.
Mitragynine (Kratom) impairs spatial learning and hippocampal synaptic transmission in rats

Hassan Z, Suhaimi FW, Ramanathan S, Ling KH, Effendy MA, Müller CP, et al.

J. Psychopharmacol. (Oxford), 2019 07;33(7):908-918.
PMID: 31081443 DOI: 10.1177/0269881119844186

BACKGROUND: Mitragynine is the major alkaloid of Mitragyna speciosa (Korth.) or Kratom, a psychoactive plant widely abused in Southeast Asia. While addictive effects of the substance are emerging, adverse cognitive effects of this drug and neuropharmacological actions are insufficiently understood.
AIMS: In the present study, we investigated the effects of mitragynine on spatial learning and synaptic transmission in the CA1 region of the hippocampus.
METHODS: Male Sprague Dawley rats received daily (for 12 days) training sessions in the Morris water maze, with each session followed by treatment either with mitragynine (1, 5, or 10 mg/kg; intraperitoneally), morphine (5 mg/kg; intraperitoneally) or a vehicle. In the second experiment, we recorded field excitatory postsynaptic potentials in the hippocampal CA1 area in anesthetized rats and assessed the effects of mitragynine on baseline synaptic transmission, paired-pulse facilitation, and long-term potentiation. Gene expression of major memory- and addiction-related genes was investigated and the effects of mitragynine on Ca2+ influx was also examined in cultured primary neurons from E16-E18 rats.
RESULTS/OUTCOMES: Escape latency results indicate that animals treated with mitragynine displayed a slower rate of acquisition as compared to their control counterparts. Further, mitragynine treatment significantly reduced the amplitude of baseline (i.e. non-potentiated) field excitatory postsynaptic potentials and resulted in a minor suppression of long-term potentiation in CA1. Bdnf and αCaMKII mRNA expressions in the brain were not affected and Ca2+ influx elicited by glutamate application was inhibited in neurons pre-treated with mitragynine.
CONCLUSIONS/INTERPRETATION: These data suggest that high doses of mitragynine (5 and 10 mg/kg) cause memory deficits, possibly via inhibition of Ca2+ influx and disruption of hippocampal synaptic transmission and long-term potentiation induction.
Kratom (M. speciosa) exposure during adolescence caused long-lasting cognitive behavioural deficits associated with perturbated brain metabolism pathways in adult rats

Suhaimi FW, Zul Aznal AN, Mohamad Nor Hazalin NA, Teh LK, Hassan Z, Salleh MZ

Behav Brain Res, 2023 May 28;446:114411.
PMID: 36997094 DOI: 10.1016/j.bbr.2023.114411

Kratom (M. speciosa Korth) is an herbal plant native to Southeast Asia. The leaves have been widely used to alleviate pain and opioid withdrawal symptoms. However, the increasing trend of recreational use of kratom among youth is concerning because substance abuse may render the adolescent brain more susceptible to neuropathological processes, causing dramatic consequences that persist into adulthood. Therefore, the present study aimed to investigate the long-term effects of mitragynine, the main alkaloid and lyophilized kratom decoction (LKD) exposure during adolescence on cognitive behaviours and brain metabolite profiles in adult rats. Adolescent male Sprague-Dawley rats were given mitragynine (3, 10 or 30 mg/kg) or LKD orally for 15 consecutive days during postnatal days 31-45 (PND31-45). Behavioural testing was performed during adulthood (PND70-84) and the brains were subjected to metabolomic analysis. The results show that a high dose of mitragynine impaired long-term object recognition memory. Social behaviour and spatial learning were not affected, but both mitragynine and LKD impaired reference memory. Brain metabolomic study revealed several altered metabolic pathways that may be involved in the cognitive behavioural effects of LKD and mitragynine exposure. These pathways include arachidonic acid, taurine and hypotaurine, pantothenate and CoA biosynthesis, and tryptophan metabolism, while the N-isovalerylglycine was identified as the potential biomarker. In summary, adolescent kratom exposure can cause long-lasting cognitive behavioural deficits and alter brain metabolite profiles that are still evident in adulthood. This finding also indicates that the adolescent brain is vulnerable to the impact of early kratom use.
Blunted endogenous GABA-mediated inhibition in the hypothalamic paraventricular nucleus of rats with streptozotocin-induced diabetes

Hassan Z, Sattar MZ, Suhaimi FW, Yusoff NH, Abdulla MH, Yusof AP, et al.

Acta Neurol Belg, 2013 Sep;113(3):319-25.
PMID: 23242937 DOI: 10.1007/s13760-012-0165-3

The hypothalamic paraventricular nucleus (PVN) is involved in the regulation of sympathetic outflow and particularly affects the heart. This study sets out to determine the role of GABA of the paraventricular nucleus (PVN) in cardiovascular regulation in streptozotocin-induced diabetic rats. Pharmacological stimulation of glutamatergic receptors with DL-Homocysteic acid (200 mM in 100 nL) in the PVN region showed a significant depression in both mean arterial pressure (MAP) and heart rate (HR) of diabetic rats (Diabetic vs. non-diabetic: MAP 15.0 ± 1.5 vs. 35.8 ± 2.8 mmHg; HR 3.0 ± 2.0 vs. 30.0 ± 6.0 bpm, P < 0.05). Microinjection of bicuculline methiodide (1 mM in 100 nL), a GABAA receptor antagonist, produced an increase in baseline MAP and HR in both non-diabetic and diabetic rats. In the diabetic rats, bicuculline injection into the PVN reduced the pressor and HR responses (Diabetic vs. non-diabetic: MAP 6.2 ± 0.8 vs. 25.1 ± 2.2 mmHg; HR 1.8 ± 1.1 vs. 25.4 ± 6.2 bpm, P < 0.05). A microinjection of muscimol (2 mM in 100 nL), which is a GABAA receptor agonist, in the PVN elicited decreases in MAP and HR in both groups. The diabetic group showed a significantly blunted reduction in HR, but not MAP (Diabetic vs. non-diabetic: MAP -15.7 ± 4.0 vs. -25.0 ± 3.8 mmHg; HR -5.2 ± 2.1 vs. -39.1 ± 7.9 bpm). The blunted vasopressor and tachycardic responses to bicuculline microinjection in the diabetic rats are likely to result from decreased GABAergic inputs, attenuated release of endogenous GABA or alterations in GABAA receptors within the PVN.
Fulltext Adolescent kratom exposure affects cognitive behaviours and brain metabolite profiles in Sprague-Dawley rats

Zul Aznal AN, Mohamad Nor Hazalin NA, Hassan Z, Mat NH, Chear NJ, Teh LK, et al.

Front Pharmacol, 2022;13:1057423.
PMID: 36518677 DOI: 10.3389/fphar.2022.1057423

Adolescence is a critical developmental period during which exposure to psychoactive substances like kratom (Mitragyna speciosa) can cause long-lasting deleterious effects. Here, we evaluated the effects of mitragynine, the main alkaloid of kratom, and lyophilised kratom decoction (LKD) on cognitive behaviours and brain metabolite profiles in adolescent rats. Male Sprague-Dawley rats (Postnatal day, PND31) were given vehicle, morphine (5 mg/kg), mitragynine (3, 10, or 30 mg/kg), or LKD (equivalent dose of 30 mg/kg mitragynine) for 15 consecutive days. Later, a battery of behavioural testing was conducted, brain was extracted and metabolomic analysis was performed using LCMS-QTOF. The results showed that mitragynine did not affect the recognition memory in the novel object recognition task. In the social interaction task, morphine, mitragynine, and LKD caused a marked deficit in social behaviour, while in Morris water maze task, mitragynine and LKD only affected reference memory. Metabolomic analysis revealed distinct metabolite profiles of animals with different treatments. Several pathways that may be involved in the effects of kratom exposure include arachidonic acid, pantothenate and CoA, and tryptophan pathways, with several potential biomarkers identified. These findings suggest that adolescent kratom exposure can cause cognitive behavioural deficits that may be associated with changes in the brain metabolite profiles.
Abuse potential and adverse cognitive effects of mitragynine (kratom)

Yusoff NH, Suhaimi FW, Vadivelu RK, Hassan Z, Rümler A, Rotter A, et al.

Addict Biol, 2016 Jan;21(1):98-110.
PMID: 25262913 DOI: 10.1111/adb.12185

Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.
Persicaria minor ameliorates the cognitive function of chronic cerebral hypoperfusion rats: Metabolomic analysis and potential mechanisms

Chun LW, Ramachandran RK, Othman SFF, Has ATC, George A, Mat NH, et al.

Behav Brain Res, 2023 Apr 06;447:114423.
PMID: 37030545 DOI: 10.1016/j.bbr.2023.114423

Persicaria minor (P. minor) is a herbal plant with many uses in food, perfume, and the medical industry. P. minor extract contains flavonoids with antioxidant and anticholinesterase capacity, which could enhance cognitive functions. P. minor extract has been proven to enhance memory. However, its role in an animal model of chronic cerebral hypoperfusion (CCH), which resembles human vascular dementia, has yet to be explored. Therefore, the present study investigates the effects of chronic (14 days) administration of aqueous P. minor extract on different stages of learning and memory processes and the metabolic pathways involved in the chronic cerebral hypoperfused rats induced by the permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery. Chronic treatment of P. minor extract at doses of 200 and 300 mg/kg, enhanced recognition memory of the PBOCCA rats. P. minor extract (200 mg/kg) was also found to restore the spatial memory impairment induced by CCH. A high dose (300 mg/kg) of the P. minor extract significantly increased the expression of both ACh and GABA neurotransmitters in the hippocampus. Further, distinctive metabolite profiles were observed in rats with different treatments. Three major pathways involved in the cognitive enhancement mechanism of P. minor were identified. The present findings demonstrated an improving effect of P. minor extract on memory in the CCH rat model, suggesting that P. minor extract could be a potential treatment for vascular dementia and Alzheimer's patients. P. minor is believed to improve cognitive deficits by regulating pathways involved in retinol, histidine, pentose, glucuronate, and CoA metabolism.
From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction

Hassan Z, Muzaimi M, Navaratnam V, Yusoff NH, Suhaimi FW, Vadivelu R, et al.

Neurosci Biobehav Rev, 2013 Feb;37(2):138-51.
PMID: 23206666 DOI: 10.1016/j.neubiorev.2012.11.012

Kratom (or Ketum) is a psychoactive plant preparation used in Southeast Asia. It is derived from the plant Mitragyna speciosa Korth. Kratom as well as its main alkaloid, mitragynine, currently spreads around the world. Thus, addiction potential and adverse health consequences are becoming an important issue for health authorities. Here we reviewed the available evidence and identified future research needs. It was found that mitragynine and M. speciosa preparations are systematically consumed with rather well defined instrumentalization goals, e.g. to enhance tolerance for hard work or as a substitute in the self-treatment of opiate addiction. There is also evidence from experimental animal models supporting analgesic, muscle relaxant, anti-inflammatory as well as strong anorectic effects. In humans, regular consumption may escalate, lead to tolerance and may yield aversive withdrawal effects. Mitragynine and its derivatives actions in the central nervous system involve μ-opioid receptors, neuronal Ca²⁺ channels and descending monoaminergic projections. Altogether, available data currently suggest both, a therapeutic as well as an abuse potential.
Evaluation of toxicity profile of kratom (Mitragyna speciosa Korth) decoction in rats

Hassan Z, Singh D, Suhaimi FW, Chear NJ, Harun N, See CP, et al.

Regul Toxicol Pharmacol, 2023 Sep;143:105466.
PMID: 37536550 DOI: 10.1016/j.yrtph.2023.105466

Mitragyna speciosa Korth also known as kratom, is an herbal drug preparation for its therapeutic properties and opioid-replacement therapy. Kratom is consumed in a brewed decoction form in Malaysia and to date, no studies have characterized its chemical and toxicity profile. Thus, this study aims to evaluate kratom decoction's safety and toxicity profile after 28 days of treatment. Mitragynine content was quantified in kratom decoction and used as a marker to determine the concentration. Male and female Sprague Dawley rats were orally treated with vehicle or kratom decoction (10, 50 or 150 mg/kg) and two satellite groups were treated with vehicle and kratom decoction (150 mg/kg). Blood and organs were collected for hematology, biochemical and histopathology analysis at the end of treatment. No mortality was found after 28 days of treatment and no significant changes in body weight and hematology profile, except for low platelet count. High amounts of uric acid, AST, ALT and alkaline phosphatase were found in the biochemical analysis. Histological investigation of the heart and lungs detected no alterations except for the kidney, liver and brain tissues. In conclusion, repeated administration of kratom decoction provided some evidence of toxicity in the kidney and liver with no occurrence of mortality.

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