Advertisement

Neurotoxicity Research

, Volume 35, Issue 2, pp 463–474 | Cite as

Effects of Cannabidiol on Diabetes Outcomes and Chronic Cerebral Hypoperfusion Comorbidities in Middle-Aged Rats

  • Amanda Nunes Santiago
  • Marco Aurélio Mori
  • Francisco Silveira Guimarães
  • Humberto Milani
  • Rúbia Maria Weffort de OliveiraEmail author
ORIGINAL ARTICLE

Abstract

Diabetes and aging are risk factors for cognitive impairments after chronic cerebral hypoperfusion (CCH). Cannabidiol (CBD) is a phytocannabinoid present in the Cannabis sativa plant. It has beneficial effects on both cerebral ischemic diseases and diabetes. We have recently reported that diabetes interacted synergistically with aging to increase neuroinflammation and memory deficits in rats subjected to CCH. The present study investigated whether CBD would alleviate cognitive decline and affect markers of inflammation and neuroplasticity in the hippocampus in middle-aged diabetic rats submitted to CCH. Diabetes was induced in middle-aged rats (14 months old) by intravenous streptozotocin (SZT) administration. Thirty days later, the diabetic animals were subjected to sham or CCH surgeries and treated with CBD (10 mg/kg, once a day) during 30 days. Diabetes exacerbated cognitive deficits induced by CCH in middle-aged rats. Repeated CBD treatment decreased body weight in both sham- and CCH-operated animals. Cannabidiol improved memory performance and reduced hippocampal levels of inflammation markers (inducible nitric oxide synthase, ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and arginase 1). Cannabidiol attenuated the decrease in hippocampal levels of brain-derived neurotrophic factor induced by CCH in diabetic animals, but it did not affect the levels of neuroplasticity markers (growth-associated protein-43 and synaptophysin) in middle-aged diabetic rats. These results suggest that the neuroprotective effects of CBD in middle-aged diabetic rats subjected to CCH are related to a reduction in neuroinflammation. However, they seemed to occur independently of hippocampal neuroplasticity changes.

Keywords

Brain ischemia Middle-aged rats Diabetes Cannabidiol Neuroprotection 

Notes

Acknowledgments

The authors thank Marco Alberto Trombelli for his technical support. This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), National Institute of Science and Translational Medicine (465458/2014-9), Universidade Estadual de Maringá.

References

  1. Akbarzadeh A, Norouzian D, Mehrabi MR, Jamshidi S, Farhangi A, Verdi AA, Mofidian SM, Rad BL (2007) Induction of diabetes by streptozotocin in rats. Indian J Clin Biochem 22:60–64CrossRefGoogle Scholar
  2. Alvarez FJ, Lafuente H, Rey-Santano MC, Mielgo VE, Gastiasoro E, Rueda M, Pertwee RG, Castillo AI, Romero J, Martinez-Orgado J (2008) Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr Res 64:653–658CrossRefGoogle Scholar
  3. Beiswenger KK, Calcutt NA, Mizisin AP (2008) Dissociation of thermal hypoalgesia and epidermal denervation in streptozotocin-diabetic mice. Neurosci Lett 442:267–272CrossRefGoogle Scholar
  4. Booz GW (2011) Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med 51:1054–1061CrossRefGoogle Scholar
  5. Braida D, Pegorini S, Arcidiacono MV, Consalez GG, Croci L, Sala M (2003) Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci Lett 346:61–64CrossRefGoogle Scholar
  6. Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30–40CrossRefGoogle Scholar
  7. Calabrese F, Guidotti G, Racagni G, Riva MA (2013) Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor. Neurobiol Aging 34:2768–2776CrossRefGoogle Scholar
  8. Campos AC, Guimaraes FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 199:223–230CrossRefGoogle Scholar
  9. Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimaraes FS (2012) Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond Ser B Biol Sci 367:3364–3378CrossRefGoogle Scholar
  10. Castillo A, Tolon MR, Fernandez-Ruiz J, Romero J, Martinez-Orgado J (2010) The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis 37:434–440CrossRefGoogle Scholar
  11. Colton C, Wilcock DM (2010) Assessing activation states in microglia. CNS Neurol Disord Drug Targets 9:174–191CrossRefGoogle Scholar
  12. Daulatzai MA (2017) Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J Neurosci Res 95:943–972CrossRefGoogle Scholar
  13. Deeds MC, Anderson JM, Armstrong AS, Gastineau DA, Hiddinga HJ, Jahangir A, Eberhardt NL, Kudva YC (2011) Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim 45:131–140CrossRefGoogle Scholar
  14. Dekel Y, Glucksam Y, Elron-Gross I, Margalit R (2009) Insights into modeling streptozotocin-induced diabetes in ICR mice. Lab Anim 38:55–60CrossRefGoogle Scholar
  15. Despres JP, Golay A, Sjostrom L, Rimonabant in Obesity-Lipids Study, G (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134CrossRefGoogle Scholar
  16. Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S, Nhieu JT, Belot MP, Zimmer A, Even P, Cani PD, Knauf C, Burcelin R, Bertola A, Le Marchand-Brustel Y, Gual P, Mallat A, Lotersztajn S (2009) Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS One 4:e5844CrossRefGoogle Scholar
  17. Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410:822–825CrossRefGoogle Scholar
  18. Dirnagl U, Endres M (2014) Found in translation: preclinical stroke research predicts human pathophysiology, clinical phenotypes, and therapeutic outcomes. Stroke 45:1510–1518CrossRefGoogle Scholar
  19. Du SQ, Wang XR, Xiao LY, Tu JF, Zhu W, He T, Liu CZ (2017) Molecular mechanisms of vascular dementia: what can be learned from animal models of chronic cerebral hypoperfusion? Mol Neurobiol 54:3670–3682CrossRefGoogle Scholar
  20. Duncombe J, Lennen RJ, Jansen MA, Marshall I, Wardlaw JM, Horsburgh K (2017) Ageing causes prominent neurovascular dysfunction associated with loss of astrocytic contacts and gliosis. Neuropathol Appl Neurobiol 43:477–491CrossRefGoogle Scholar
  21. El-Remessy AB, Al-Shabrawey M, Khalifa Y, Tsai NT, Caldwell RB, Liou GI (2006) Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am J Pathol 168:235–244CrossRefGoogle Scholar
  22. El-Remessy AB, Khalifa Y, Ola S, Ibrahim AS, Liou GI (2010) Cannabidiol protects retinal neurons by preserving glutamine synthetase activity in diabetes. Mol Vis 16:1487–1495PubMedPubMedCentralGoogle Scholar
  23. Ergul A, Hafez S, Fouda A, Fagan SC (2016) Impact of comorbidities on acute injury and recovery in preclinical stroke research: focus on hypertension and diabetes. Transl Stroke Res 7:248–260CrossRefGoogle Scholar
  24. Esposito G, Filippis DD, Cirillo C, Iuvone T, Capoccia E, Scuderi C, Steardo A, Cuomo R, Steardo L (2013) Cannabidiol in inflammatory bowel diseases: a brief overview. Phytother Res 27:633–636CrossRefGoogle Scholar
  25. Ferreira ED, Romanini CV, Mori MA, de Oliveira RM, Milani H (2011) Middle-aged, but not young, rats develop cognitive impairment and cortical neurodegeneration following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion. Eur J Neurosci 34:1131–1140CrossRefGoogle Scholar
  26. Fischer DC, Nissel R, Puhlmann A, Mitzner A, Tiess M, Schmidt R, Haffner D (2009) Differential effects of short-term growth hormone therapy on the cardiovascular risk profile in patients with chronic kidney disease: a pilot study. Clin Nephrol 72:344–352CrossRefGoogle Scholar
  27. Gaspar JM, Baptista FI, Macedo MP, Ambrosio AF (2016) Inside the diabetic brain: role of different players involved in cognitive decline. ACS Chem Neurosci 7:131–142CrossRefGoogle Scholar
  28. Gomes RM, de Paulo LF, Bonato Panizzon C, Neves CQ, Cordeiro BC, Zanoni JN, Francisco FA, Piovan S, de Freitas Mathias PC, Longhini R, de Mello JCP, de Oliveira JC, Pedrino GR, da Silva Reis AA, Cecchini AL, Marcal Natali MR (2017) Anti-diabetic effects of the ethyl-acetate fraction of Trichilia catigua in streptozo-tocin-induced type 1 diabetic rats. Cell Physiol Biochem 42:1087–1097CrossRefGoogle Scholar
  29. Gruden G, Barutta F, Kunos G, Pacher P (2016) Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol 173:1116–1127CrossRefGoogle Scholar
  30. Gruneberg D, Montellano FA, Plaschke K, Li L, Marti HH, Kunze R (2016) Neuronal prolyl-4-hydroxylase 2 deficiency improves cognitive abilities in a murine model of cerebral hypoperfusion. Exp Neurol 286:93–106CrossRefGoogle Scholar
  31. Harry GJ (2013) Microglia during development and aging. Pharmacol Ther 139:313–326CrossRefGoogle Scholar
  32. Hayakawa K, Mishima K, Irie K, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Katsurabayashi S, Takasaki K, Iwasaki K, Fujiwara M (2008) Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism. Neuropharmacology 55:1280–1286CrossRefGoogle Scholar
  33. Hayakawa K, Irie K, Sano K, Watanabe T, Higuchi S, Enoki M et al. (2009) Therapeutic time window of cannabidiol treatment on delayed ischemic damage via high-mobility group box1-inhibiting mechanism. Biol Pharm Bull 32:1538–1544Google Scholar
  34. Ho N, Sommers MS, Lucki I (2013) Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev 37:1346–1362CrossRefGoogle Scholar
  35. Horvath B, Mukhopadhyay P, Hasko G, Pacher P (2012) The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications. Am J Pathol 180:432–442CrossRefGoogle Scholar
  36. Hu Y, Zhang M, Chen Y, Yang Y, Zhang JJ (2018) Postoperative intermittent fasting prevents hippocampal oxidative stress and memory deficits in a rat model of chronic cerebral hypoperfusion. Eur J NutrGoogle Scholar
  37. Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808CrossRefGoogle Scholar
  38. Ignatowska-Jankowska B, Jankowski MM, Swiergiel AH (2011) Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci Lett 490:82–84CrossRefGoogle Scholar
  39. Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, O'Sullivan SE, Tan GD (2016) Efficacy and safety of cannabidiol and tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel group pilot study. Diabetes Care 39:1777–1786CrossRefGoogle Scholar
  40. Jeon WJ, Oh JS, Park MS, Ji GE (2013) Anti-hyperglycemic effect of fermented ginseng in type 2 diabetes mellitus mouse model. Phytother Res 27:166–172CrossRefGoogle Scholar
  41. Jourdan T, Godlewski G, Kunos G (2016) Endocannabinoid regulation of beta-cell functions: implications for glycaemic control and diabetes. Diabetes Obes Metab 18:549–557CrossRefGoogle Scholar
  42. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:13435–13444CrossRefGoogle Scholar
  43. Koellhoffer EC, McCullough LD, Ritzel RM (2017) Old maids: aging and its impact on microglia function. Int J Mol Sci 18Google Scholar
  44. Kunos G, Tam J (2011) The case for peripheral CB(1) receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol 163:1423–1431CrossRefGoogle Scholar
  45. Lafuente H, Alvarez FJ, Pazos MR, Alvarez A, Rey-Santano MC, Mielgo V, Murgia-Esteve X, Hilario E, Martinez-Orgado J (2011) Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatr Res 70:272–277CrossRefGoogle Scholar
  46. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172:4790–4805CrossRefGoogle Scholar
  47. Liu HX, Zhang JJ, Zheng P, Zhang Y (2005) Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Brain Res Mol Brain Res 139:169–177CrossRefGoogle Scholar
  48. Liu H, Zhang J, Yang Y, Zhang L, Zeng X (2012) Decreased cerebral perfusion and oxidative stress result in acute and delayed cognitive impairment. Curr Neurovasc Res 9(3):152–158Google Scholar
  49. Liu Z, Hu M, Lu P, Wang H, Qi Q, Xu J, Xiao Y, Fan M, Jia Y, Zhang D (2017) Cerebrolysin alleviates cognitive deficits induced by chronic cerebral hypoperfusion by increasing the levels of plasticity-related proteins and decreasing the levels of apoptosis-related proteins in the rat hippocampus. Neurosci Lett 651:72–78CrossRefGoogle Scholar
  50. Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V (2006) Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 91:3171–3180CrossRefGoogle Scholar
  51. Matouk AI, Taye A, El-Moselhy MA, Heeba GH, Abdel-Rahman AA (2008) Abnormal cannabidiol confers cardioprotection in diabetic rats independent of glycemic control. Eur J Pharmacol pp 256–264Google Scholar
  52. McKillop AM, Moran BM, Abdel-Wahab YH, Gormley NM, Flatt PR (2016) Metabolic effects of orally administered small-molecule agonists of GPR55 and GPR119 in multiple low-dose streptozotocin-induced diabetic and incretin-receptor-knockout mice. Diabetologia 59:2674–2685CrossRefGoogle Scholar
  53. Mechoulam R, Gaoni Y (1965) Hashish. IV. The isolation and structure of cannabinolic cannabidiolic and cannabigerolic acids. Tetrahedron 21:1223–1229CrossRefGoogle Scholar
  54. Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (2007) Cannabidiol—recent advances. Chem Biodivers 4:1678–1692CrossRefGoogle Scholar
  55. Minnerup J, Wersching H, Teuber A, Wellmann J, Eyding J, Weber R, Reimann G, Weber W, Krause LU, Kurth T, Berger K, Investigators, R (2016) Outcome after thrombectomy and intravenous thrombolysis in patients with acute ischemic stroke: a prospective observational study. Stroke 47:1584–1592CrossRefGoogle Scholar
  56. Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M (2005) Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 36:1077–1082CrossRefGoogle Scholar
  57. Mori MA, Meyer E, Soares LM, Milani H, Guimaraes FS, de Oliveira RMW (2017) Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia. Prog Neuro-Psychopharmacol Biol Psychiatry 75:94–105CrossRefGoogle Scholar
  58. Morrison CD, Pistell PJ, Ingram DK, Johnson WD, Liu Y, Fernandez-Kim SO, White CL, Purpera MN, Uranga RM, Bruce-Keller AJ, Keller JN (2010) High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem 114:1581–1589CrossRefGoogle Scholar
  59. Nishijima Y, Akamatsu Y, Yang SY, Lee CC, Baran U, Song S, Wang RK, Tominaga T, Liu J (2016) Impaired collateral flow compensation during chronic cerebral hypoperfusion in the type 2 diabetic mice. Stroke 47:3014–3021CrossRefGoogle Scholar
  60. Nunes Santiago A, Dias Fiuza Ferreira E, Weffort de Oliveira RM, Milani H (2018) Cognitive, neurohistological and mortality outcomes following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion: the impact of diabetes and aging. Behav Brain Res 339:169–178CrossRefGoogle Scholar
  61. Pazos MR, Mohammed N, Lafuente H, Santos M, Martinez-Pinilla E, Moreno E, Valdizan E, Romero J, Pazos A, Franco R, Hillard CJ, Alvarez FJ, Martinez-Orgado J (2013) Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. Neuropharmacology 71:282–291CrossRefGoogle Scholar
  62. Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol. 1–51Google Scholar
  63. Pertwee RG (2008a) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215CrossRefGoogle Scholar
  64. Pertwee RG (2008b) Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr Med Che 17:1360–1381Google Scholar
  65. Polidori MC, Pientka L, Mecocci P (2012) A review of the major vascular risk factors related to Alzheimer's disease. J Alzheimers Dis 32(3):521–530Google Scholar
  66. Popa-Wagner A, Glavan DG, Olaru A, Olaru DG, Margaritescu O, Tica O, Surugiu R, Sandu RE (2018) Present status and future challenges of new therapeutic targets in preclinical models of stroke in aged animals with/without comorbidities. Int J Mol Sci 19Google Scholar
  67. Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Drel VR, Obrosova IG, Pacher P (2007) Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol 293:H610–H619CrossRefGoogle Scholar
  68. Rajesh M, Mukhopadhyay P, Batkai S, Patel V, Saito K, Matsumoto S, Kashiwaya Y, Horvath B, Mukhopadhyay B, Becker L, Hasko G, Liaudet L, Wink DA, Veves A, Mechoulam R, Pacher P (2010) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol 56:2115–2125CrossRefGoogle Scholar
  69. Schiavon AP, Soares LM, Bonato JM, Milani H, Guimaraes FS, Weffort de Oliveira RM (2014) Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice. Neurotox Res 26:307–316CrossRefGoogle Scholar
  70. Schoeder CT, Kaleta M, Mahardhika AB, Olejarz-Maciej A, Łażewska D, Kieć-Kononowicz K, Müller CE (2018) Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18. Eur J Med Chem 15(55):381–397Google Scholar
  71. Scopinho AA, Guimaraes FS, Correa FM, Resstel LB (2011) Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists. Pharmacol Biochem Behav 98:268–272CrossRefGoogle Scholar
  72. Shang J, Yamashita T, Zhai Y, Nakano Y, Morihara R, Fukui Y, Hishikawa N, Ohta Y, Abe K (2016) Strong impact of chronic cerebral hypoperfusion on neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling in Alzheimer's disease model mouse. J Alzheimer’s Dis 52:113–126CrossRefGoogle Scholar
  73. Shetty AK, Hattiangady B, Rao MS, Shuai B (2011) Deafferentation enhances neurogenesis in the young and middle aged hippocampus but not in the aged hippocampus. Hippocampus 21:631–646CrossRefGoogle Scholar
  74. Straiker A, Dvorakova M, Zimmowitch A, Mackie KP (2018) Cannabidiol inhibits endocannabinoid signaling in autaptic hippocampal neurons. Mol Pharmacol 94:743–748CrossRefGoogle Scholar
  75. Sweetnam D, Holmes A, Tennant KA, Zamani A, Walle M, Jones P, Wong C, Brown CE (2012) Diabetes impairs cortical plasticity and functional recovery following ischemic stroke. J Neurosci 32:5132–5143CrossRefGoogle Scholar
  76. Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, Makriyannis A, Kunos G (2010) Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 120:2953–2966CrossRefGoogle Scholar
  77. Valerio Romanini C, Dias Fiuza Ferreira E, Correia Bacarin C, Verussa MH, Weffort de Oliveira RM, Milani H (2013) Neurohistological and behavioral changes following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats. Behav Brain Res 252:214–221CrossRefGoogle Scholar
  78. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, Group, R.I.-E.S (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389–1397CrossRefGoogle Scholar
  79. van Harten B, Oosterman J, Muslimovic D, van Loon BJ, Scheltens P, Weinstein HC (2007) Cognitive impairment and MRI correlates in the elderly patients with type 2 diabetes mellitus. Age Ageing 36:164–170CrossRefGoogle Scholar
  80. Wang X, Xing A, Xu C, Cai Q, Liu H, Li L (2010) Cerebrovascular hypoperfusion induces spatial memory impairment, synaptic changes, and amyloid-beta oligomerization in rats. J Alzheimers Dis 21:813–822CrossRefGoogle Scholar
  81. Weiss L, Zeira M, Reich S, Har-Noy M, Mechoulam R, Slavin S, Gallily R (2006) Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39:143–151CrossRefGoogle Scholar
  82. Weiss L, Zeira M, Reich S, Slavin S, Raz I, Mechoulam R, Gallily R (2008) Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology 54:244–249CrossRefGoogle Scholar
  83. Wongchitrat P, Lansubsakul N, Kamsrijai U, Sae-Ung K, Mukda S, Govitrapong P (2016) Melatonin attenuates the high-fat diet and streptozotocin-induced reduction in rat hippocampal neurogenesis. Neurochem Int 100:97–109CrossRefGoogle Scholar
  84. Wu KK, Huan Y (2008) Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol Chapter 5(Unit 5):47PubMedGoogle Scholar
  85. Wu Z, Wang H, Ni F, Jiang X, Xu Z, Liu C, Cai Y, Fu H, Luo J, Chen W, Chen B, Yu Z (2018) Islet transplantation improved penile tissue fibrosis in a rat model of type 1 diabetes. BMC Endocrine disorders, 27, 18(1):49Google Scholar
  86. Yang Y, Gao L (2017) Celecoxib alleviates memory deficits by downregulation of COX-2 expression and upregulation of the BDNF-TrkB signaling pathway in a diabetic rat model. J Mol Neurosci 62:188–198CrossRefGoogle Scholar
  87. Zanoni JN, Buttow NC, Bazotte RB, Miranda Neto MH (2003) Evaluation of the population of NADPH-diaphorase-stained and myosin-V myenteric neurons in the ileum of chronically streptozotocin-diabetic rats treated with ascorbic acid. Auton Neurosci 104:32–38CrossRefGoogle Scholar
  88. Zhang X, Gao S, Niu J, Li P, Deng J, Xu S, Wang Z, Wang W, Kong D, Li C (2016) Cannabinoid 2 receptor agonist improves systemic sensitivity to insulin in high-fat diet/streptozotocin-induced diabetic mice. Cell Physiol Biochem 40:1175–1185CrossRefGoogle Scholar
  89. Zuloaga KL, Johnson LA, Roese NE, Marzulla T, Zhang W, Nie X, Alkayed FN, Hong C, Grafe MR, Pike MM, Raber J, Alkayed NJ (2016) High fat diet-induced diabetes in mice exacerbates cognitive deficit due to chronic hypoperfusion. J Cereb Blood Flow Metab 36:1257–1270CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Amanda Nunes Santiago
    • 1
  • Marco Aurélio Mori
    • 1
  • Francisco Silveira Guimarães
    • 2
  • Humberto Milani
    • 1
  • Rúbia Maria Weffort de Oliveira
    • 1
    Email author
  1. 1.Department of Pharmacology and TherapeuticsState University of MaringáMaringáBrazil
  2. 2.Centre for Interdisciplinary Research on Applied Neurosciences (NPNA), Department of Pharmacology, Medical School of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil

Personalised recommendations