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Beneficial effects of buspirone in endothelin-1 induced stroke cachexia in rats

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Abstract

Stroke cachexia is associated with prolonged inflammation, muscle loss, poor prognosis, and early death of stroke patients. No particular treatment is available to cure the symptoms or disease. The present study aimed to evaluate the effect of a 5-HT1a agonist, buspirone on stroke cachexia. Wistar rats were injected with endothelin-1 to the bregma region of the brain to induce ischemic stroke followed by induction of cachexia after 4 days. Treatment with buspirone (3 mg/kg p.o) was given for 4 weeks after confirmation of cachexia in animals. Disease control animals exhibited decrease in wire hanging time and increase in foot fault numbers compared to normal animals. Disease control animals also showed weight loss, decrease in food intake, increased serum glucose and lipid profile along with high serum levels of inflammatory cytokines—TNF-α, IL-6 and decrease in weight of skeletal muscle and adipose tissues. Treatment with buspirone improves behavioural parameters along with increases food intake and body weight, decreased inflammatory cytokines IL-6 and TNF-α and serum glucose levels with increase in lipid profile. Buspirone also increased the weight of adipose tissue and maintain the skeletal muscle architecture and function as depicted in histopathological studies. Our study suggests that buspirone produces beneficial role in stroke cachexia by increasing body weight, food intake and adipose tissue depots by activating on 5-HT receptors. Buspirone decreases inflammatory markers in stroke cachexia although mechanism behind it was not fully understood. Buspirone decreases circulating blood glucose by stimulating glucose uptake in skeletal muscle via 5-HT receptors and maintained lipid profile. Buspirone was found to be effective in ameliorating cachectic conditions in stroke.

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Abbreviations

5-HT :

5-Hydroxytryptamine

CXCL1 :

Chemokine (C-X-C motif) ligand 1

ECM :

Extracellular matrix

ET-1 :

Endothelin-1

EDL :

Extensor digitorum longus

HDL :

High density protein

HE :

Haematoxylin and Eosin

IL-6 :

Intraleukin-6

LDL :

Low density protein

MCA :

Middle cerebral artery

MT :

Masson trichrome

SE :

Picro sirius red

TNF-α :

Tumor necrosis factor-α

References

  1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Statistics C and Stroke Statistics S (2017) Heart disease and stroke statistics-2017 update: a Report from the American Heart Association. Circulation 135:e146–e603. https://doi.org/10.1161/CIR.0000000000000485

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gorelick PB (2019) The global burden of stroke: persistent and disabling. Lancet Neurol 18:417–418. https://doi.org/10.1016/S1474-4422(19)30030-4

    Article  PubMed  Google Scholar 

  3. Scherbakov N, Pietrock C, Sandek A, Ebner N, Valentova M, Springer J, Schefold JC, von Haehling S, Anker SD, Norman K, Haeusler KG, Doehner W (2019) Body weight changes and incidence of cachexia after stroke. J Cachexia Sarcopenia Muscle 10:611–620. https://doi.org/10.1002/jcsm.12400

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ni J, Zhang L (2020) Cancer Cachexia: Definition, Staging, and Emerging Treatments. Cancer Manag Res 12:5597–5605. https://doi.org/10.2147/CMAR.S261585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bouziana SD, Tziomalos K (2011) Malnutrition in patients with acute stroke. J Nutr Metab. https://doi.org/10.1155/2011/167898

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dziedzic T (2015) Systemic inflammation as a therapeutic target in acute ischemic stroke. Expert Rev Neurother 15:523–531. https://doi.org/10.1586/14737175.2015.1035712

    Article  CAS  PubMed  Google Scholar 

  7. Rosa Neto JC, Lira FS, Roy S, Festuccia W (2017) Immunometabolism: molecular mechanisms, diseases, and therapies 2016. Mediators Inflamm 2017:8230298. https://doi.org/10.1155/2017/8230298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chevalier S, Farsijani S (2014) Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment. Appl Physiol Nutr Metab 39:643–653. https://doi.org/10.1139/apnm-2013-0369

    Article  CAS  PubMed  Google Scholar 

  9. von Haehling S, Anker SD (2015) Treatment of cachexia: an overview of recent developments. Int J Cardiol 184:736–742. https://doi.org/10.1016/j.ijcard.2014.10.026

    Article  Google Scholar 

  10. Dill MJ, Shaw J, Cramer J, Sindelar DK (2013) 5-HT1A receptor antagonists reduce food intake and body weight by reducing total meals with no conditioned taste aversion. Pharmacol Biochem Behav 112:1–8. https://doi.org/10.1016/j.pbb.2013.09.003

    Article  CAS  PubMed  Google Scholar 

  11. Fletcher PJ, Davies M (1990) Dorsal raphe microinjection of 5-HT and indirect 5-HT agonists induces feeding in rats. Eur J Pharmacol 184:265–271. https://doi.org/10.1016/0014-2999(90)90618-g

    Article  CAS  PubMed  Google Scholar 

  12. Wilson TK and Tripp J (2021) Buspirone. StatPearls, Treasure Island (FL)

  13. Thomas Broome S, Fisher T, Faiz A, Keay KA, Musumeci G, Al-Badri G, Castorina A (2021) Assessing the anti-inflammatory activity of the anxiolytic drug buspirone using CRISPR-Cas9 gene editing in LPS-stimulated BV-2 microglial cells. Cells. https://doi.org/10.3390/cells10061312

    Article  PubMed  PubMed Central  Google Scholar 

  14. Abeysinghe HCS, Roulston CL (2018) A complete guide to using the endothelin-1 model of stroke in conscious rats for acute and long-term recovery studies. Methods Mol Biol 1717:115–133. https://doi.org/10.1007/978-1-4939-7526-6_10

    Article  CAS  PubMed  Google Scholar 

  15. Martins LA, Schiavo A, Xavier LL, Mestriner RG (2022) The Foot Fault Scoring System to Assess Skilled Walking in Rodents: A Reliability Study. Front Behav Neurosci 16:892010. https://doi.org/10.3389/fnbeh.2022.892010

    Article  PubMed  PubMed Central  Google Scholar 

  16. Thong-Asa W, Jedsadavitayakol S, Jutarattananon S (2021) Benefits of betanin in rotenone-induced Parkinson mice. Metab Brain Dis 36:2567–2577. https://doi.org/10.1007/s11011-021-00826-0

    Article  CAS  PubMed  Google Scholar 

  17. Martinez-Huenchullan SF, McLennan SV, Ban LA, Morsch M, Twigg SM, Tam CS (2017) Utility and reliability of non-invasive muscle function tests in high-fat-fed mice. Exp Physiol 102:773–778. https://doi.org/10.1113/EP086328

    Article  CAS  PubMed  Google Scholar 

  18. Morley JE, Thomas DR, Wilson MM (2006) Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 83:735–743. https://doi.org/10.1093/ajcn/83.4.735

    Article  CAS  PubMed  Google Scholar 

  19. Deans C, Wigmore SJ (2005) Systemic inflammation, cachexia and prognosis in patients with cancer. Curr Opin Clin Nutr Metab Care 8:265–269. https://doi.org/10.1097/01.mco.0000165004.93707.88

    Article  CAS  PubMed  Google Scholar 

  20. de Matos-Neto EM, Lima JD, de Pereira WO, Figueredo RG, Riccardi DM, Radloff K, das Neves RX, Camargo RG, Maximiano LF, Tokeshi F, Otoch JP, Goldszmid R, Camara NO, Trinchieri G, de Alcantara PS, Seelaender M (2015) Systemic inflammation in cachexia - is tumor cytokine expression profile the culprit? Front Immunol 6:629. https://doi.org/10.3389/fimmu.2015.00629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Masi T, Patel BM (2021) Altered glucose metabolism and insulin resistance in cancer-induced cachexia: a sweet poison. Pharmacol Rep 73:17–30. https://doi.org/10.1007/s43440-020-00179-y

    Article  CAS  PubMed  Google Scholar 

  22. Sassoon DA (2016) Fatty acid metabolism-the first trigger for cachexia? Nat Med 22:584–585. https://doi.org/10.1038/nm.4121

    Article  CAS  PubMed  Google Scholar 

  23. Bowen TS, Schuler G, Adams V (2015) Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. J Cachexia Sarcopenia Muscle 6:197–207. https://doi.org/10.1002/jcsm.12043

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chen R, Lei S, Jiang T, She Y, Shi H (2020) Regulation of skeletal muscle atrophy in cachexia by MicroRNAs and Long Non-coding RNAs. Front Cell Dev Biol 8:577010. https://doi.org/10.3389/fcell.2020.577010

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang C, Yue F, Kuang S (2017) Muscle Histology characterization using H&E staining and muscle fiber type classification using immunofluorescence staining. Bio Protoc. https://doi.org/10.21769/BioProtoc.2279

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rieppo L, Janssen L, Rahunen K, Lehenkari P, Finnila MAJ, Saarakkala S (2019) Histochemical quantification of collagen content in articular cartilage. PLoS ONE 14:e0224839. https://doi.org/10.1371/journal.pone.0224839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lattouf R, Younes R, Lutomski D, Naaman N, Godeau G, Senni K, Changotade S (2014) Picrosirius red staining: a useful tool to appraise collagen networks in normal and pathological tissues. J Histochem Cytochem 62:751–758. https://doi.org/10.1369/0022155414545787

    Article  CAS  PubMed  Google Scholar 

  28. Van De Vlekkert D, Machado E, d’Azzo A (2020) Analysis of generalized fibrosis in mouse tissue sections with Masson’s trichrome staining. Bio Protoc 10:e3629. https://doi.org/10.21769/BioProtoc.3629

    Article  PubMed  Google Scholar 

  29. Franca CM, de Loura SC, Takahashi CB, Alves AN, De Souza Mernick AP, Fernandes KP, de Fatima Teixeira da SD, Bussadori SK, Mesquita-Ferrari RA (2013) Effect of laser therapy on skeletal muscle repair process in diabetic rats. Lasers Med Sci 28:1331–1338. https://doi.org/10.1007/s10103-012-1249-2

    Article  PubMed  Google Scholar 

  30. Wilkinson LO, Jacobs BL (1988) Lack of response of serotonergic neurons in the dorsal raphe nucleus of freely moving cats to stressful stimuli. Exp Neurol 101:445–457. https://doi.org/10.1016/0014-4886(88)90055-6

    Article  CAS  PubMed  Google Scholar 

  31. Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ (2016) Endothelin. Pharmacol Rev 68:357–418. https://doi.org/10.1124/pr.115.011833

    Article  PubMed  PubMed Central  Google Scholar 

  32. Balkaya M, Krober JM, Rex A, Endres M (2013) Assessing post-stroke behavior in mouse models of focal ischemia. J Cereb Blood Flow Metab 33:330–338. https://doi.org/10.1038/jcbfm.2012.185

    Article  CAS  PubMed  Google Scholar 

  33. Silvestrin RB, de Oliveira LF, Batassini C, Oliveira A, e Souza TM, (2009) The footfault test as a screening tool in the 6-hydroxydopamine rat model of Parkinson’s disease. J Neurosci Methods 177:317–321. https://doi.org/10.1016/j.jneumeth.2008.10.030

    Article  CAS  PubMed  Google Scholar 

  34. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ (1994) Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25:1481–1488. https://doi.org/10.1161/01.str.25.7.1481

    Article  CAS  PubMed  Google Scholar 

  35. Pawluk H, Wozniak A, Grzesk G, Kolodziejska R, Kozakiewicz M, Kopkowska E, Grzechowiak E, Kozera G (2020) The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke. Clin Interv Aging 15:469–484. https://doi.org/10.2147/CIA.S233909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Webster JM, Kempen L, Hardy RS, Langen RCJ (2020) Inflammation and skeletal muscle wasting during cachexia. Front Physiol 11:597675. https://doi.org/10.3389/fphys.2020.597675

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kim JK, Han SK, Joo MK, Kim DH (2021) Buspirone alleviates anxiety, depression, and colitis; and modulates gut microbiota in mice. Sci Rep 11:6094. https://doi.org/10.1038/s41598-021-85681-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sharifi H, Nayebi AM, Farajnia S, Haddadi R (2015) Effect of chronic administration of buspirone and fluoxetine on inflammatory cytokines in 6-hydroxydopamine-lesioned rats. Drug Res (Stuttg) 65:393–397. https://doi.org/10.1055/s-0034-1374615

    Article  CAS  PubMed  Google Scholar 

  39. Tisdale MJ (2000) Metabolic abnormalities in cachexia and anorexia. Nutrition 16:1013–1014. https://doi.org/10.1016/s0899-9007(00)00409-3

    Article  CAS  PubMed  Google Scholar 

  40. Dodesini AR, Benedini S, Terruzzi I, Sereni LP, Luzi L (2007) Protein, glucose and lipid metabolism in the cancer cachexia: a preliminary report. Acta Oncol 46:118–120. https://doi.org/10.1080/02841860600791491

    Article  CAS  PubMed  Google Scholar 

  41. Kruyt ND, Biessels GJ, Devries JH, Roos YB (2010) Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management. Nat Rev Neurol 6:145–155. https://doi.org/10.1038/nrneurol.2009.231

    Article  CAS  PubMed  Google Scholar 

  42. Mantovani G, Maccio A, Massa E, Madeddu C (2001) Managing cancer-related anorexia/cachexia. Drugs 61:499–514. https://doi.org/10.2165/00003495-200161040-00004

    Article  CAS  PubMed  Google Scholar 

  43. Ago T, Matsuo R, Hata J, Wakisaka Y, Kuroda J, Kitazono T, Kamouchi M, Fukuoka Stroke Registry I (2018) Insulin resistance and clinical outcomes after acute ischemic stroke. Neurology 90:e1470–e1477. https://doi.org/10.1212/WNL.0000000000005358

    Article  CAS  PubMed  Google Scholar 

  44. Chang Y, Kim CK, Kim MK, Seo WK, Oh K (2021) Insulin resistance is associated with poor functional outcome after acute ischemic stroke in non-diabetic patients. Sci Rep 11:1229. https://doi.org/10.1038/s41598-020-80315-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Raghunathan S, Tank P, Bhadada S, Patel B (2014) Evaluation of buspirone on streptozotocin induced type 1 diabetes and its associated complications. Biomed Res Int 2014:948427. https://doi.org/10.1155/2014/948427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ojha SK, Nandave M, Sharma C (2006) Effect of buspirone: An anxiolytic drug on blood glucose in humans. Indian J Clin Biochem 21:58–62. https://doi.org/10.1007/BF02912913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hajduch E, Rencurel F, Balendran A, Batty IH, Downes CP, Hundal HS (1999) Serotonin (5-Hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle. J Biol Chem 274:13563–13568. https://doi.org/10.1074/jbc.274.19.13563

    Article  CAS  PubMed  Google Scholar 

  48. Kotler DP (2000) Cachexia. Ann Intern Med 133:622–634. https://doi.org/10.7326/0003-4819-133-8-200010170-00015

    Article  CAS  PubMed  Google Scholar 

  49. Laurens C, Moro C (2016) Intramyocellular fat storage in metabolic diseases. Horm Mol Biol Clin Investig 26:43–52. https://doi.org/10.1515/hmbci-2015-0045

    Article  CAS  PubMed  Google Scholar 

  50. Bharosay A, Bharosay VV, Bandyopadhyay D, Sodani A, Varma M, Baruah H (2014) Effect of lipid profile upon prognosis in ischemic and haemorrhagic cerebrovascular stroke. Indian J Clin Biochem 29:372–376. https://doi.org/10.1007/s12291-013-0372-6

    Article  CAS  PubMed  Google Scholar 

  51. Tatidis L, Vitols S, Gruber A, Paul C, Axelson M (2001) Cholesterol catabolism in patients with acute myelogenous leukemia and hypocholesterolemia: suppressed levels of a circulating marker for bile acid synthesis. Cancer Lett 170:169–175. https://doi.org/10.1016/s0304-3835(01)00592-4

    Article  CAS  PubMed  Google Scholar 

  52. Sun X, Feng X, Wu X, Lu Y, Chen K, Ye Y (2020) Fat wasting is damaging: role of adipose tissue in cancer-associated cachexia. Front Cell Dev Biol 8:33. https://doi.org/10.3389/fcell.2020.00033

    Article  PubMed  PubMed Central  Google Scholar 

  53. Haley MJ, Mullard G, Hollywood KA, Cooper GJ, Dunn WB, Lawrence CB (2017) Adipose tissue and metabolic and inflammatory responses to stroke are altered in obese mice. Dis Model Mech 10:1229–1243. https://doi.org/10.1242/dmm.030411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ung RV, Rouleau P, Guertin PA (2012) Functional and physiological effects of treadmill training induced by buspirone, carbidopa, and L-DOPA in clenbuterol-treated paraplegic mice. Neurorehabil Neural Repair 26:385–394. https://doi.org/10.1177/1545968311427042

    Article  PubMed  Google Scholar 

  55. Rausch V, Sala V, Penna F, Porporato PE, Ghigo A (2021) Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia. Oncogenesis 10:1. https://doi.org/10.1038/s41389-020-00288-6

    Article  PubMed  PubMed Central  Google Scholar 

  56. Guillet-Deniau I, Burnol AF, Girard J (1997) Identification and localization of a skeletal muscle secrotonin 5-HT2A receptor coupled to the Jak/STAT pathway. J Biol Chem 272:14825–14829. https://doi.org/10.1074/jbc.272.23.14825

    Article  CAS  PubMed  Google Scholar 

  57. Kliewer KL, Ke JY, Tian M, Cole RM, Andridge RR, Belury MA (2015) Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice. Cancer Biol Ther 16:886–897. https://doi.org/10.4161/15384047.2014.987075

    Article  CAS  PubMed  Google Scholar 

  58. McClement S (2021) Adipose tissue and cancer cachexia: what nurses need to know. Asia Pac J Oncol Nurs 8:445–449. https://doi.org/10.4103/apjon.apjon-2134

    Article  PubMed  PubMed Central  Google Scholar 

  59. Vaitkus JA, Celi FS (2017) The role of adipose tissue in cancer-associated cachexia. Exp Biol Med (Maywood) 242:473–481. https://doi.org/10.1177/1535370216683282

    Article  CAS  PubMed  Google Scholar 

  60. Csapo R, Gumpenberger M, Wessner B (2020) Skeletal muscle extracellular matrix - what do we know about its composition, regulation, and physiological roles? A Narrative Rev Front Physiol 11:253. https://doi.org/10.3389/fphys.2020.00253

    Article  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the kind help of Mr. Pallav Gandhi (Research Scholar) in the administration of endothelin-1 using stereotaxic apparatus.

Funding

This study was supported by Nirma University, Gujarat, India as a minor research project.

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Authors and Affiliations

  1. Institute of Pharmacy, Nirma University, Ahmedabad, India

    Darshak Shah, Mit Joshi & Jigna Shah

  2. National Forensic Sciences University, Sector 9, Gandhinagar, Gujarat, 382007, India

    Bhoomika M. Patel

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Contributions

DS prepared the study plan, executed experiments, interpreted and analyzed the data; MJ executed analytical parameters, and prepared the manuscript; JS Guided for study protocol, data interpretation and manuscript writing; BMP was involved in conceptualization of the idea, designing of the study, arranging the funds, guiding for study protocol, data interpretation and manuscript writing and approved the manuscript.

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Correspondence to Bhoomika M. Patel.

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The protocol of the experiment was approved by the institutional animal ethical committee as per the guidance of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of fisheries, Government of India. (IP/PCOL/MPH/28/2021/001).

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Shah, D., Joshi, M., Shah, J. et al. Beneficial effects of buspirone in endothelin-1 induced stroke cachexia in rats. Mol Cell Biochem 478, 2069–2080 (2023). https://doi.org/10.1007/s11010-022-04653-4

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