Sains Malaysiana 50(3)(2021): 779-790

http://doi.org/10.17576/jsm-2021-5003-19

 

Anorectic Effect, Biochemical and Hematological Profiles of Alkaloid Extract from Mitragyna speciosa Korth. in Rats

(Kesan Anorektik, Profil Biokimia dan Hematologi Ekstrak Alkaloid daripada Mitragyna speciosa Korth. dalam Tikus)

 

EKKASIT KUMARNSIT1,2,3, NIWAT KEAWPRADUB4, NARUMON SENGNON4, JURAITHIP WUNGSINTAWEEKUL4 & DANIA CHEAHA2,5*

 

1Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90112, Thailand

 

2Biosignal Research Center for Health, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90112, Thailand

3The Natural Product Research Center of Excellence, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90112, Thailand 

 

4Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hatyai, Songkhla 90112, Thailand

 

5Division of Biological Science, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90112, Thailand  

 

 

Received: 24 April 2019/Accepted: 18 August 2020

 

ABSTRACT

There is an on-going debate about medicinal use of kratom plant (Mitragyna speciosa (MS)) on whether it has beneficial or adverse effects. This study aimed to examine long-term weight-reducing effects, toxicity, and dopamine pathway activation of MS alkaloid extract on adult male Wistar rats. In anorexic study, the rats were divided into 3 groups (n = 10), receiving intragastric administration once a day for 19 weeks as control (distilled water), chronic (20 mg/kg MS alkaloid extract) and withdrawal (20 mg/kg MS alkaloid extract for week 1-12 and distilled water for week 13-19) groups. Body weights were measured daily, and blood samples were collected at the end of study for biochemical and hematological tests. In immunohistochemistry, the effects of the extract (40 and 80 mg/kg) on the nucleus accumbens (NAc) and striatum (STr) were determined by using Fos-like immunoreactivity. From week 2 to 19, the results showed a significant reduction in body weight gain produced by the extract. Cessation of the treatment at week 12 did not result in a rebound weight gain. Chronic MS alkaloid extract treatment significantly decreased non-fasting blood sugar, triglyceride, uric acid and blood urea nitrogen (BUN). However, elevated SGOT may suggest possible hepatotoxicity. Chronic MS alkaloid extract treatment also produced baseline levels for most of the hematological parameters except a decrease of monocyte. In immunohistochemistry, the acute treatment did not induce Fos-like immunoreactivity in the NAc and STr. These data demonstrated the beneficial effects of the MS alkaloid extract for possible treatment of metabolic syndromes without toxicity and rewarding effect.

 

Keywords: Addiction; anorectic; kratom; Mitragyna speciosa; toxicity

 

ABSTRAK

Terdapat perbahasan berterusan mengenai penggunaan tanaman kratom (Mitragyna speciosa (MS)) sebagai ubat, sama ada ia memberikan kesan yang baik atau buruk. Kajian ini bertujuan untuk mengkaji kesan pengurangan berat badan jangka panjang, ketoksikan dan pengaktifan jalur dopamin ekstrak alkaloid MS pada tikus Wistar jantan dewasa. Dalam kajian anoreksik, tikus dibahagikan kepada 3 kumpulan (n = 10), iaitu kumpulan kawalan yang menerima pemberian intragastrik sekali sehari selama 19 minggu sebagai kawalan (air suling), kumpulan kronik (20 mg/kg MS alkaloid ekstrak) dan kumpulan penarikan (20 mg/kg ekstrak alkaloid MS untuk minggu 1-12 dan air suling untuk minggu 13-19). Berat badan diukur setiap hari dan sampel darah dikumpulkan pada akhir kajian untuk ujian biokimia dan hematologi. Dalam keimunan-histokimia, kesan ekstrak (40 dan 80 mg/kg) pada nukleus akumbens (NAc) dan striatum (STr) ditentukan dengan menggunakan reaktiviti imun mirip-Fos. Dari minggu 2 hingga 19, terdapat penurunan ketara dalam kenaikan berat badan yang dihasilkan oleh ekstrak tersebut. Penghentian rawatan pada minggu ke-12 tidak menyebabkan kenaikan berat badan. Rawatan ekstrak alkaloid MS kronik menurunkan gula darah tanpa puasa, trigliserida, asid urik dan nitrogen urea darah (BUN). Walau bagaimanapun, kenaikan SGOT mungkin menunjukkan kemungkinan kehepatotoksidan. Rawatan ekstrak alkaloid MS kronik juga menghasilkan tahap garis dasar bagi kebanyakan parameter hematologi kecuali penurunan monosit. Dalam keimunan-histokimia, rawatan akut tidak menyebabkan reaktiviti imun mirip-Fos pada NAc dan STr. Data ini menunjukkan kesan yang baik daripada ekstrak alkaloid MS untuk kemungkinan rawatan sindrom metabolik tanpa ketoksikan dan kesan ganjaran.

 

Kata kunci: Anorektik; ketagihan; ketoksikan; kratom; Mitragyna speciose

 

REFERENCES

Ahlskog, J.E. & Hoebel, B.G. 1973. Overeating and obesity from damage to a noradrenergic system in the brain. Science 182: 166-169.

Ahrold, T.K. & Meston, C.M. 2009. Effects of SNS activation on SSRI-induced sexual side effects differ by SSRI. Journal of Sex & Marital Therapy 35(4): 311-319.

Apryani, E., Taufik Hidayat, M., Moklas, M.A.A., Fakurazi, S. & Farah Idayu, N. 2010. Effects of mitragynine from Mitragyna speciosa Korth leaves on working memory. Journal of Ethnopharmacology 129(3): 357-360.

Bitsch, M. & Skrumsager, B.K. 1987. Femoxetine in the treatment of obese patients in general practice. A randomized group comparative study with placebo. International Journal of Obesity 11(2): 183-190.

Capaldi, V.F. & Carr, R.B. 2010. Citalopram-induced hallucinations and delusions in a young adult. General Hospital Psychiatry 32(6): 648.e1-648.e3.

Chakroun, S., Ezzi, L., Grissa, I., Kerkeni, E., Neffati, F., Bhouri, R., Sallem, A., Najjar, M.F., Hassine, M., Mehdi, M., Haouas, Z. & Ben Cheikh, H. 2016. Hematological, biochemical, and toxicopathic effects of subchronic acetamiprid toxicity in Wistar rats. Environmental Science and Pollution Research 23(24): 25191-25199.

Cheaha, D., Reakkamnuan, C., Nukitram, J., Chittrakarn, S., Phukpattaranont, P., Keawpradub, N. & Kumarnsit, E. 2017. Effects of alkaloid-rich extract from Mitragyna speciosa (Korth.) Havil. on naloxone-precipitated morphine withdrawal symptoms and local field potential in the nucleus accumbens of mice. Journal of Ethnopharmacology 208: 129-137.

Cheaha, D., Keawpradub, N., Sawangjaroen, K., Phukpattaranont, P. & Kumarnsit, E. 2015. Effects of an alkaloid-rich extract from Mitragyna speciosa leaves and fluoxetine on sleep profiles, EEG spectral frequency and ethanol withdrawal symptoms in rats. Phytomedicine 22(11): 1000-1008.

Ding, W. & Mak, R.H. 2015. Early markers of obesity-related renal injury in childhood. Pediatric Nephrology 30(1): 1-4.

Doherty, J.M. & Frantz, K.J. 2012. Heroin self-administration and reinstatement of heroin-seeking in adolescent vs. adult male rats. Psychopharmacology 219(3): 763-773.

Edge, J.P. & Gold, S.M. 2012. Drug withdrawal and hyperphagia: Lessons from tobacco and other drugs. Current Pharmaceutical Design 17(12): 1173-1179.

Farah Idayu, N., Taufik Hidayat, M., Moklas, M.A.M., Sharida, F., Nurul Raudzah, A.R., Shamima, A.R. & Apryani, E. 2011. Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression. Phytomedicine 18(5): 402-407.

Gallagher, E.J., LeRoith, D. & Karnieli, E. 2010. Insulin resistance in obesity as the underlying cause for the metabolic syndrome. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 77(5): 511-523.

Graybiel, A.M., Moratalla, R. & Robertson, H.A. 1990. Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proceedings of the National Academy of Sciences of the United States of America 87(17). pp. 6912-6916.

Gursoy, A., Erdogan, M.F., Cin, M.O., Cesur, M. & Baskal, N. 2006. Comparison of orlistat and sibutramine in an obesity management program: Efficacy compliance, and weight regain after noncompliance. Eating and Weight Disorders 11(4): e127-e132.

Harizal, S.N., Mansor, S.M., Hasnan, J., Tharakan, J.K.J. & Abdullah, J. 2010. Acute toxicity study of the standardized methanolic extract of Mitragyna speciosa Korth in Rodent. Journal of Ethnopharmacology 131(2): 404-409.

Harms, R., Morsey, B., Boyer, C.W., Fox, H.S. & Sarvetnick, N. 2012. Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression. PLoS ONE 7(12): e49897.

Harun, N., Hassan, Z., Navaratnam, V., Mansor, S.M. & Shoaib, M. 2015. Discriminative stimulus properties of mitragynine (kratom) in rats. Psychopharmacology 232(13): 2227-2238.

Himmelstein, D.U., Woolhandler, S.J. & Adler, R.D. 1984. Elevated SGOT/SGPT ratio in alcoholic patients with acetaminophen hepatotoxicity. The American Journal of Gastroenterology 79(9): 718-720.

Horie, S., Koyama, F., Takayama, H., Ishikawa, H., Aimi, N., Ponglux, D., Matsumoto, K. & Murayama, T. 2005. Indole alkaloids of a Thai medicinal herb, Mitragyna speciosa, that has opioid agonistic effect in guinea-pig ileum. Planta Medica 71(3): 231-236.

Hyman, S.E. 1996. Addiction to cocaine and amphetamine. Neuron 16(5): 901-904.

Ito, Y., Kobuchi, S., Shimizu, R. & Katsuyama, Y. 2018. Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats. Cancer Chemotherapy and Pharmacology 81(1): 155-161.

Janardhan, K.S., Sandhu, S.K. & Singh, B. 2006. Neutrophil depletion inhibits early and late monocyte/macrophage increase in lung inflammation. Frontiers in Bioscience 11: 1569-1576.

Jansen, K.L.R. & Prast, C.J. 1988. Psychoactive properties of mitragynine (Kratom). Journal of Psychoactive Drugs 20(4): 455-457.

Karaduman, D., Sarioglu-Buke, A., Kilic, I. & Gurses, E. 2003. The role of elevated liver transaminase levels in children with blunt abdominal trauma. Injury 34(4): 249-252.

Kumarnsit, E., Vongvatcharanon, U., Keawpradub, N. & Intasaro, P. 2007. Fos-like immunoreactivity in rat dorsal raphe nuclei induced by alkaloid extract of Mitragyna speciosa. Neuroscience Letters 416(2): 128-132.

Kumarnsit, E., Keawpradub, N. & Nuankaew, W. 2006. Acute and long-term effects of alkaloid extract of Mitragyna speciosa on food and water intake and body weight in rats. Fitoterapia 77(5): 339-345.

Kumarnsit, E., Harnyuttanakorn, P., Meksuriyen, D., Govitrapong, P., Baldwin, B.A., Kotchabhakdi, N. & Casalotti, S.O. 1999. Pseudoephedrine, a sympathomimetic agent, induces Fos-like immunoreactivity in rat nucleus accumbens and striatum. Neuropharmacology 38(9): 1381-1387.

Leshem, M. 1981. Morphine-induced anorexia in lateral hypothalamic rats. Psychopharmacology 75(1): 48-53.

Limsuwanchote, S., Putalun, W., Keawpradub, N., Tanaka, H., Morimoto, S. & Wungsintaweekul, J. 2017. Anti-mitragynine monoclonal antibody-based ELISA for determination of alkaloids in the kratom cocktail. Forensic Toxicology 35(1): 167-172.

Liu, Y., Morgan, D. & Roberts, D.C.S. 2007. Cross-sensitization of the reinforcing effects of cocaine and amphetamine in rats. Psychopharmacology 195(3): 369-375.

Matsumoto, K., Horie, S., Ishikawa, H., Takayama, H., Aimi, N., Ponglux, D. & Watanabe, K. 2004. Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa. Life Sciences 74(17): 2143-2155.

Matsumoto, K., Mizowaki, M., Suchitra, T., Murakami, Y., Takayama, H., Sakai, S.I., Aimi, N. & Watanabe, H. 1996. Central antinociceptive effects of mitragynine in mice: Contribution of descending noradrenergic and serotonergic systems. European Journal of Pharmacology 317(1): 75-81.

McElroy, S.L., Hudson, J.I., Malhotra, S., Welge, J.A., Nelson, E.B. & Keck, P.E. 2003. Citalopram in the treatment of binge-eating disorder: A placebo-controlled trial. The Journal of Clinical Psychiatry 64(7): 807-813.

McGuirk, J., Muscat, R. & Willner, P. 1992. Effects of chronically administered fluoxetine and fenfluramine on food intake, body weight and the behavioural satiety sequence. Psychopharmacology 106(3): 401-407.

Nathan, P.J. & Bullmore, E.T. 2009. From taste hedonics to motivational drive: Central-opioid receptors and binge-eating behaviour. The International Journal of Neuropsychopharmacology 12: 995-1008.

Pifl, C., Drobny, H., Reither, H., Hornykiewicz, O. & Singer, E.A. 1995. Mechanism of the dopamine-releasing actions of amphetamine and cocaine: Plasmalemmal dopamine transporter versus vesicular monoamine transporter. Molecular Pharmacology 47(2): 368-373.

Ponglux, D., Wongseripipatana, S., Takayama, H., Kikuchi, M., Kurihara, M., Kitajima, M., Aimi, N. & Sakai, S. 1994. A new indole alkaloid, 7α-hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand. Planta Medica 60(6): 580-581.

Purintrapiban, J., Keawpradub, N., Kansenalak, S., Chittrakarn, S., Janchawee, B. & Sawangjaroen, K. 2011. Study on glucose transport in muscle cells by extracts from Mitragyna speciosa (Korth) and mitragynine. Natural Product Research 25(15): 1379-1387.

Ruksee, N., Tongjaroenbuangam, W., Casalotti, S.O. & Govitrapong, P. 2008. Amphetamine and pseudoephedrine cross-tolerance measured by c-Fos protein expression in brains of chronically treated rats. BMC Neuroscience 9: 1-8.

Sabetghadam, A., Ramanathan, S., Sasidharan, S. & Mansor, S.M. 2013. Subchronic exposure to mitragynine, the principal alkaloid of Mitragyna speciosa, in rats. Journal of Ethnopharmacology 146(3): 815-823.

Seiden, L.S., Sabol, K.E. & Ricaurte, G.A. 1993. Amphetamine: Effects on catecholamine systems and behavior. Annual Review of Pharmacology and Toxicology 33: 639-677.

Sharp, T., Zetterström, T., Ljungberg, T. & Ungerstedt, U. 1987. A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis. Brain Research 401(2): 322-330.

Sufka, K.J., Loria, M.J., Lewellyn, K., Zjawiony, J.K., Ali, Z., Abe, N. & Khan, I.A. 2014. The effect of Salvia divinorum and Mitragyna speciosa extracts, fraction and major constituents on place aversion and place preference in rats. Journal of Ethnopharmacology 151(1): 361-364.

Sussman, N., Ginsberg, D.L. & Bikoff, J. 2001. Effects of nefazodone on body weight: A pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials. Journal of Clinical Psychiatry 62(4): 256-260.

Takayama, H., Ishikawa, H., Kurihara, M., Kitajima, M., Aimi, N., Ponglux, D., Koyama, F., Matsumoto, K., Moriyama, T., Yamamoto, L.T., Watanabe, K., Murayama, T. & Horie, S. 2002. Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: Discovery of opioid agonists structurally different from other opioid ligands. Journal of Medicinal Chemistry 45(9): 1949-1956.

Takayama, K., Suzuki, T. & Miura, M. 1994. The comparison of effects of various anesthetics on expression of Fos protein in the rat brain. Neuroscience Letters 176(1): 59-62.

Wiffen, P.J., Derry, S. & Moore, R.A. 2014. Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain. Cochrane Database of Systematic Reviews 5(CD011056): 1-111.

Yusoff, N.H.M., Suhaimi, F.W., Vadivelu, R.K., Hassan, Z., Rümler, A., Rotter, A., Amato, D., Dringenberg, H.C., Mansor, S.M., Navaratnam, V. & Müller, C.P. 2016. Abuse potential and adverse cognitive effects of mitragynine (kratom). Addiction Biology 21(1): 98-110.

Zhao, Q., Yang, Z.S., Cao, S.J., Chang, Y.F., Cao, Y.Q., Li, J.B., Yao, Z.X., Wen, Y.P., Huang, X.B., Wu, R., Yan, Q.G., Huang, Y., Ma, X.P., Han, X.F. & Wu, Y. 2019. Acute oral toxicity test and assessment of combined toxicity of cadmium and aflatoxin B1 in kunming mice. Food and Chemical Toxicology 131(2019): 110577.

 

*Corresponding author; email: dania.c@psu.ac.th

 

 

       

 

previous