Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities


The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population. Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy. Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed. In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.

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  1. 1.

    Trinka E, Kalviainen R (2017) 25 years of advances in the definition, classification and treatment of status epilepticus. Seizure 44:65–73.

    PubMed  Article  Google Scholar 

  2. 2.

    Fountain NB (2000) Status epilepticus: risk factors and complications. Epilepsia 41(s2):S23–S30.

    PubMed  Article  Google Scholar 

  3. 3.

    Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA (1998) Incidence of status epilepticus in Rochester, Minnesota, 1965-1984. Neurology 50(3):735–741.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Menon R, Radhakrishnan A, Radhakrishnan K (2013) Status epilepticus. J Assoc Physicians India 61(8 Suppl):58–63

    PubMed  Google Scholar 

  5. 5.

    Betjemann JP, Lowenstein DH (2015) Status epilepticus in adults. Lancet Neurol 14(6):615–624.

    PubMed  Article  Google Scholar 

  6. 6.

    Sanchez S, Rincon F (2016) Status epilepticus: epidemiology and public health needs. J Clin Med 5(8):71.

    PubMed Central  Article  Google Scholar 

  7. 7.

    Trinka E, Brigo F, Shorvon S (2016) Recent advances in status epilepticus. Curr Opin Neurol 29:189–198

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Loscher W (2017) The search for new screening models of pharmacoresistant epilepsy: is induction of acute seizures in epileptic rodents a suitable approach? Neurochem Res 42(7):1926–1938.

    PubMed  CAS  Article  Google Scholar 

  9. 9.

    Hattiangady B, Kuruba R, Shetty AK (2011) Acute seizures in old age leads to a greater loss of CA1 pyramidal neurons, an increased propensity for developing chronic TLE and a severe cognitive dysfunction. Aging Dis 2:1–17

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Mishra V, Shuai B, Kodali M, Shetty GA, Hattiangady B, Rao X, Shetty AK (2015) Resveratrol treatment after status epilepticus restrains neurodegeneration and abnormal neurogenesis with suppression of oxidative stress and inflammation. Sci Rep 5(17807)

  11. 11.

    Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17(10):3727–3738

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Pauletti A, Terrone G, Shekh-AhmadT SA, Ravizza T, Rizzi M et al (2017) Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain 140(7):1885–1899.

    PubMed  Article  Google Scholar 

  13. 13.

    Rao MS, Hattiangady B, Reddy DS, Shetty AK (2006) Hippocampal neurodegeneration, spontaneous seizures, and mossy fiber sprouting in the F344 rat model of temporal lobe epilepsy. J Neurosci Res 83(6):1088–1105.

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Rao MS, Hattiangady B, Shetty AK (2008) Status epilepticus during old age is not associated with enhanced hippocampal neurogenesis. Hippocampus 18(9):931–944.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Pitkänen A, Engel J Jr (2014) Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics 11:231–241

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Hattiangady B, Rao MS, Shetty AK (2004) Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis 17(3):473–490.

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Hattiangady B, Shetty AK (2010) Decreased neuronal differentiation of newly generated cells underlies reduced hippocampal neurogenesis in chronic temporal lobe epilepsy. Hippocampus 20(1):97–112.

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Rotheneichner P, Marschallinger J, Couillard-Despres S, Aigner L (2013) Neurogenesis and neuronal regeneration in status epilepticus. Epilepsia 54:40–42.

    PubMed  Article  Google Scholar 

  19. 19.

    Scharfman HE, Gray WP (2007) Relevance of seizure-induced neurogenesis in animal models of epilepsy to the etiology of temporal lobe epilepsy. Epilepsia 48(s2):33–41.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Shetty AK (2014) Hippocampal injury-induced cognitive and mood dysfunction, altered neurogenesis, and epilepsy: can early neural stem cell grafting intervention provide protection? Epilepsy Behav 38:117–124.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Buckmaster PS (2014) Does mossy fiber sprouting give rise to the epileptic state? Adv Exp Med Biol 813:161–168.

    PubMed  Article  Google Scholar 

  22. 22.

    Koyama R (2016) Dentate circuitry as a model to study epileptogenesis. Biol Pharm Bull 39(6):891–896.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Shetty AK, Zaman V, Hattiangady B (2005) Repair of the injured adult hippocampus through graft-mediated modulation of the plasticity of the dentate gyrus in a rat model of temporal lobe epilepsy. J Neurosci 25:8391–8401

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Shetty AK, Turner DA (1997) Fetal hippocampal cells grafted to kainate-lesioned CA3 region of adult hippocampus suppress aberrant supragranular sprouting of host mossy fibers. Exp Neurol 143(2):231–245.

    PubMed  CAS  Article  Google Scholar 

  25. 25.

    Shetty AK, Turner DA (1999) Aging impairs axonal sprouting response of dentate granule cells following target loss and partial deafferentation. J Comp Neurol 414(2):238–254.<238::AID-CNE7>3.0.CO;2-A

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Shetty AK, Turner DA (2000) Fetal hippocampal grafts containing CA3 cells restore host hippocampal glutamate decarboxylase-positive interneuron numbers in a rat model of temporal lobe epilepsy. J Neurosci 20(23):8788–8801

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Shetty AK, Hattiangady B, Rao MS (2009) Vulnerability of hippocampal GABA-ergic interneurons to kainate-induced excitotoxic injury during old age. J Cell Mol Med 13:2408–2423

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Marx M, Haas CA, Haussler U (2013) Differential vulnerability of interneurons in the epileptic hippocampus. Front Cell Neurosci 7(167).

  29. 29.

    Buckmaster PS, Abrams E, Wen X (2017) Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy. J Comp Neurol 525:2592–2610

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  30. 30.

    Szczurowska E, Mares P (2013) NMDA and AMPA receptors: development and status epilepticus. Physiol Res 62:S21–S38

    PubMed  CAS  Google Scholar 

  31. 31.

    Scharfman HE, Brooks-Kayal AR (2014) Is plasticity of GABAergic mechanisms relevant to epileptogenesis? Adv Exp Med Biol 813:133–150.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Qian F, Tang FR (2016) Metabotropic glutamate receptors and interacting proteins in epileptogenesis. Curr Neuropharmacol 14(5):551–562.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  33. 33.

    Coulter DA, Steinhauser C (2015) Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med 5(3):a022434.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  34. 34.

    Rowley S, Patel M (2013) Mitochondrial involvement and oxidative stress in temporal lobe epilepsy. Free Radic Biol Med 62:121–131.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  35. 35.

    Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7(1):31–40.

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Vezzani A, Lang B, Aronica E (2015) Immunity and inflammation in epilepsy. Cold Spring Harb Perspect Med 6:a022699

    PubMed  Article  Google Scholar 

  37. 37.

    Orcinha C, Munzner G, Gerlach J, Kilias A, Follo M, Egert U, Haas CA (2016) Seizure-induced motility of differentiated dentate granule cells is prevented by the central Reelin fragment. Front Cell Neurosci 10:183

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Blumcke I, Thom M, Aronica E, Armstrong DD, Bartolomei F, Bernasconi A et al (2013) International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 54(7):1315–1329.

    PubMed  Article  Google Scholar 

  39. 39.

    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, di Marzo V et al (2014) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55(6):791–802.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  40. 40.

    Peixoto-Santos JE, Velasco TR, Galvis-Alonso OY, Araujo D, Kandratavicius L, Assirati JA, Carlotti CG, Scandiuzzi RC et al (2015) Temporal lobe epilepsy patients with severe hippocampal neuron loss but normal hippocampal volume: extracellular matrix molecules are important for the maintenance of hippocampal volume. Epilepsia 56(10):1562–1570.

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Rodrigues GR, Kandratavicius L, Peixoto-Santos JE, Monteiro MR, Gargaro AC, Geraldi Cde V, Velasco TR, Leite JP (2015) Increased frequency of hippocampal sclerosis ILAE type 2 in patients with mesial temporal lobe epilepsy with normal episodic memory. Brain 138(6):e359.

    PubMed  Article  Google Scholar 

  42. 42.

    Abel EL (1980) Marihuana: the first twelve thousand years. Plenum Press, New York.

    Google Scholar 

  43. 43.

    Brill H (1981) Marihuana: the first twelve thousand years. J Psychoactive Drugs 13(4):397–398.

    PubMed  Article  Google Scholar 

  44. 44.

    Solimini R, Rotolo MC, Pichini S, Pacifici R (2017) Neurological disorders in medical use of cannabis: an update. CNS Neurol Disord Drug Targets 16(5):527–533.

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    Steenkamp MM, Blessing EM, Galatzer-Levy IR, Hollahan LC, Anderson WT (2017) Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: a literature review. Depress Anxiety 34(3):207–216.

    PubMed  Article  Google Scholar 

  46. 46.

    Tkaczyk M, Florek E, Piekoszewski W (2012) Marihuana and cannobinoids as medicaments. Przegl Lek 69:1095–1097

    PubMed  Google Scholar 

  47. 47.

    ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A (2017) Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod 103:1–36.

    PubMed  CAS  Article  Google Scholar 

  48. 48.

    Elsohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78(5):539–548.

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Nickels K (2017) Cannabidiol in patients with intractable epilepsy due to TSC: a possible medication but not a miracle. Epilepsy Curr 17(2):91–92.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34(5):605–613

    PubMed  CAS  Google Scholar 

  51. 51.

    Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 87(5):1932–1936.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  52. 52.

    Lupica CR, Hu Y, Devinsky O, Hoffman AF (2017) Cannabinoids as hippocampal network administrators. Neuropharmacology 124:25–37.

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29(7):2053–2063.

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Chesher GB, Jackson DM, Malor RM (1975) Interaction of delta 9-tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice from electrically induced convulsions. J Pharm Pharmacol 27(8):608–609.

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Consroe P, Benedito MA, Leite JR, Carlini EA, Mechoulam R (1982) Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol 83(3-4):293–298.

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    Hosseinzadeh M, Nikseresht S, Khodagholi F, Naderi N, Maghsoudi N (2016) Cannabidiol post-treatment alleviates rat epileptic-related behaviors and activates hippocampal cell autophagy pathway along with antioxidant defense in chronic phase of pilocarpine-induced seizure. J Mol Neurosci 58:432–440

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Izquierdo I, Orsingher OA, Berardi AC (1973) Effect of cannabidiol and of other cannabis sativa compounds on hippocampal seizure discharges. Psychopharmacologia 28(1):95–102.

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Jones NA, Glyn SE, Akiyama S, Hill TD, Hill AJ, Weston SE (2012) Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure 21(5):344–352.

    PubMed  Article  Google Scholar 

  59. 59.

    Rosenberg EC, Patra PH, Whalley BJ (2017) Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav 70(Pt B):319–327.

    PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Mao K, You C, Lei D, Zhang H (2015) High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect. Int J Clin Exp Med 15:8820–8827

    Google Scholar 

  61. 61.

    Kaplan JS, Stella N, Catterall WA, Westenbroek RE (2017) Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 114(42):11229–11234.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  62. 62.

    Alvarez FJ, Lafuente H, Rey-Santano MC, Mielgo VE, Gastiasoro E, Rueda M (2008) Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr Res 64(6):653–658.

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Do Val-da Silva RA, Peixoto-Santos JE, Kandratavicius L, De Ross JB, Esteves I, De Martinis BS, Alves MNR, Scandiuzzi RC et al (2017) Protective effects of cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy. Front Pharmacol 8(131)

  64. 64.

    Porter BE, Jacobson C (2013) Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav 29(3):574–577.

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Hussain SA, Zhou R, Jacobson C, Weng J, Cheng E, Lay J, Hung P, Lerner JT et al (2015) Perceived efficacy of cannabidiol-enriched cannabis extracts fortreatment of pediatric epilepsy: a potential role for infantile spasms andLennox-Gastaut syndrome. Epilepsy Behav 47:138–141.

    PubMed  Article  Google Scholar 

  66. 66.

    Press CA, Knupp KG, Chapman KE (2015) Parental reporting of response to oralcannabis extracts for treatment of refractory epilepsy. Epilepsy Behav 45:49–52.

    PubMed  Article  Google Scholar 

  67. 67.

    Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB et al (2016) CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure 35:41–44.

    PubMed  Article  Google Scholar 

  68. 68.

    Aguirre-Velázquez CG (2017) Report from a survey of parents regarding the use of cannabidiol (Medicinal cannabis) in Mexican children with refractory epilepsy. Neurol Res Int 2017(2985729):1–5.

    Article  Google Scholar 

  69. 69.

    Suraev AS, Todd L, Bowen MT, Allsop DJ, McGregor IS, Ireland C, Lintzeris N (2017) An Australian nationwide survey on medicinal cannabis use for epilepsy: history of antiepileptic drug treatment predicts medicinal cannabis use. Epilepsy Behav 70(Pt B):334–340.

    PubMed  Article  Google Scholar 

  70. 70.

    Treat L, Chapman KE, Colborn KL, Knupp KG (2017) Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients. Epilepsia 58(1):123–127.

    PubMed  CAS  Article  Google Scholar 

  71. 71.

    Mathern GW, Beninsig L, Nehlig A (2015) Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia’s survey. Epilepsia 56:1–6

    PubMed  Article  Google Scholar 

  72. 72.

    Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R et al (2016) Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 15(3):270–278.

    PubMed  CAS  Article  Google Scholar 

  73. 73.

    Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, Paolini JL, Thiele EA (2016) Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 57(10):1617–1624.

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Kaplan EH, Offermann EA, Sievers JW, Comi AM (2017) Cannabidiol treatment for refractory seizures in Sturge-Weber syndrome. Pediatr Neurol 71:18–23.

    PubMed  Article  Google Scholar 

  75. 75.

    Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA et al (2017) Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 376(21):2011–2020.

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Ridler C (2017) Epilepsy: cannabidiol reduces seizure frequency in Dravet syndrome. Nat Rev Neurol 13(7):383.

    PubMed  Article  Google Scholar 

  77. 77.

    O’Connell BK, Gloss D, Devinsky O (2017) Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav 70:341–348

    PubMed  Article  Google Scholar 

  78. 78.

    Warren PP, Bebin EM, Nabors LB, Szaflarski JP (2017) The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy. Neurocase 23(5-6):287–291.

    PubMed  Article  Google Scholar 

  79. 79.

    Saade D, Joshi C (2015) Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatr Neurol 52:544–547

    PubMed  Article  Google Scholar 

  80. 80.

    Crippa JA, Crippa AC, Hallak JE, Martín-Santos R, Zuardi AW (2016) Δ9-THC intoxication by cannabidiol-enriched cannabis extract in two children with refractory epilepsy: full remission after switching to purified cannabidiol. Front Pharmacol 7(359).

  81. 81.

    Verrotti A, Carrozzino D, Milioni M, Minna M, Fulcheri M (2014) Epilepsy and its main psychiatric comorbidities in adults and children. J Neurol Sci 343:23–29

    PubMed  Article  Google Scholar 

  82. 82.

    Rao G, Mashkouri S, Aum D, Marcet P, Borlongan CV (2017) Contemplating stem cell therapy for epilepsy-induced neuropsychiatric symptoms. Neuropsychiatr Dis Treat 13:585–596

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Rosenberg EC, Louik J, Conway E, Devinsky O, Friedman D (2017) Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia 58:96–100

    Article  Google Scholar 

  84. 84.

    Gomes FV, Resstel LB, Guimarães FS (2011) The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 213(2-3):465–473.

    PubMed  CAS  Article  Google Scholar 

  85. 85.

    Klein BD, Jacobson CA, Metcalf CS, Smith MD, Wilcox KS, Hampson AJ, Kehne JH (2017) Evaluation of cannabidiol in animal seizure models by the Epilepsy Therapy Screening Program (ETSP). Neurochem Res 42(7):1939–1948.

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, Laux L, Marsh ED (2017) Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol 32(1):35–40.

    PubMed  Article  Google Scholar 

  87. 87.

    Geffrey AL, Pollack SF, Bruno PL, Thiele EA (2015) Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 56:246–251

    Article  Google Scholar 

  88. 88.

    Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP (2017) UAB CBD program interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 58(9):1586–1592.

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O (2015) Cannabinoids and epilepsy. Neurotherapeutics 12(4):747–768.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  90. 90.

    Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50(1):83–90.

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215(1):89–97.

    PubMed  CAS  Article  Google Scholar 

  92. 92.

    Elmes MW, Kaczocha M, Berger WT, Leung K, Ralph BP, Wang L et al (2015) Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 290(14):8711–8721.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  93. 93.

    Vilela LR, Lima IV, Kunsch ÉB, Pinto HPP, de Miranda AS, Vieira ÉLM, de Oliveira ACP, Moraes MFD et al (2017) Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels. Epilepsy Behav 75:29–35.

    PubMed  Article  Google Scholar 

  94. 94.

    Llano I, Marty A, Armstrong CM, Konnerth A (1991) Synaptic- and agonist-induced excitatory currents of Purkinje cells in rat cerebellar slices. J Physiol 434(1):183–213.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  95. 95.

    Pitler TA, Alger BE (1992) Postsynaptic spike firing reduces synaptic GABAA responses in hippocampal pyramidal cells. J Neurosci 12(10):4122–4132

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Katona I, Freund TF (2008) Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 14(9):923–930.

    PubMed  CAS  Article  Google Scholar 

  97. 97.

    Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mackie K, Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Melis M, Pistis M, Perra S, Muntoni AL, Pillolla G, Gessa GL (2004) Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci 24(1):53–62.

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Kawamura Y, Fukaya M, Maejima T, Yoshida T, Miura E, Watanabe M, Ohno-Shosaku T, Kano M (2006) The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci 26(11):2991–3001.

    PubMed  CAS  Article  Google Scholar 

  100. 100.

    Marsicano G, Lutz B (2006) Neuromodulatory functions of the endocannabinoid system. J Endocrinol Investig 29(3 Suppl):27–46

    CAS  Google Scholar 

  101. 101.

    Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ (2010) Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther 332(2):569–577.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  102. 102.

    Thomas BF, Gilliam AF, Burch DF, Roche MJ, Seltzman HH (1998) Comparative receptor binding analyses of cannabinoid agonists and antagonists. J Pharmacol Exp Ther 285(1):285–292

    PubMed  CAS  Google Scholar 

  103. 103.

    Sylantyev S, Jensen TP, Ross RA, Rusakov DA (2013) Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci U S A 110(13):5193–5198.

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Shirazi-zand Z, Ahmad-Molaei L, Motamedi F, Naderi N (2013) The role of potassium BK channels in anticonvulsant effect of cannabidiol in pentylenetetrazole andmaximal electroshock models of seizure in mice. Epilepsy Behav 28(1):1–7.

    PubMed  Article  Google Scholar 

  105. 105.

    Patel RR, Barbosa C, Brustovetsky T, Brustovetsky N, Cummins TR (2016) Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain 139:2164–2181

    PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Hill AJ, Jones NA, Smith I, Hill CL, Williams CM, Stephens GJ, Whalley BJ (2014) Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se. Neurosci Lett 30:269–274

    Article  Google Scholar 

  107. 107.

    Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E et al (2014) Non psychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 19:1131–1141

    Article  Google Scholar 

  108. 108.

    Carrier EJ, Auchampach JA, Hillard CJ (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 103(20):7895–7900.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  109. 109.

    Pandolfo P, Silveirinha V, dos Santos-Rodrigues A, Venance L, Ledent C, Takahashi RN, Cunha RA, Kofalvi A (2011) Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum. Eur J Pharmacol 655(1-3):38–45.

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    De Petrocellis L, Di Marzo V (2010) Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. J NeuroImmune Pharmacol 5(1):103–121.

    PubMed  Article  Google Scholar 

  111. 111.

    Booz GW (2011) Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med 51(5):1054–1061.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  112. 112.

    Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu AX et al (2013) Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 52:1079–1087

    Article  Google Scholar 

  113. 113.

    Hill TD, Cascio MG, Romano B, Duncan M, Pertwee RG, Williams CM, Whalley BJ, Hill AJ (2013) Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 170(3):679–692.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  114. 114.

    Vilela LR, Gomides LF, David BA, Antunes MM, Diniz AB, Moreira Fde A, Menezes GB (2015) Cannabidiol rescues acute hepatic toxicity and seizure induced by cocaine. Mediat Inflamm.

  115. 115.

    Liou GI, Auchampach JA, Hillard CJ, Zhu G, Yousufzai B, Mian S, Khan S, Khalifa Y (2008) Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor. Invest Ophthalmol Vis Sci 49(12):5526–5531.

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Mecha M, Torrao AS, Mestre L, Carrillo-Salinas FJ, Mechoulam R, Guaza C (2012) Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress. Cell Death Dis 28:e331

    Article  Google Scholar 

  117. 117.

    Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24

    PubMed  CAS  Article  Google Scholar 

  118. 118.

    Shimada T, Takemiya T, Sugiura H, Yamagata K (2014) Role of inflammatory mediators in the pathogenesis of epilepsy. Mediat Inflamm 2014:1–8.

    CAS  Article  Google Scholar 

  119. 119.

    Acosta SA, Tajiri N, Hoover J, Kaneko Y, Borlongan CV (2015) Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke 46: 2616–2627

  120. 120.

    Lozano D, Gonzales-Portillo GS, Acosta S, de la Pena I, Tajiri N, Kaneko Y, Borlongan CV (2015) Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat 11:97–106.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  121. 121.

    Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353(6301):777–783.

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    Long Q, Upadhya D, Kim DK, Hattiangady B, An SY, Prockop DJ, Shetty AK (2017) Intranasal MSC-derived A1-exosomes ease inflammation, and preventabnormal neurogenesis and memory dysfunction after status epilepticus. Proc Natl Acad Sci U S A 114:E3536–E3545

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  123. 123.

    Rubio M, Valdeolivas S, Piscitelli F, Verde R, Satta V, Barroso E, Montolio M, Aras LM et al (2016) Analysis of endocannabinoid signaling elements and related proteins in lymphocytes of patients with Dravet syndrome. Pharmacol Res Perspect 4(00220):e00220.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  124. 124.

    Gobira PH, Vilela LR, Gonçalves BD, Santos RP, de Oliveira AC, Vieira LB et al (2015) Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release. Neurotoxicology 50:116–121.

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    Esposito G, Scuderi C, Savani C, Steardo L Jr, De Filippis D, Cottone P et al (2007) Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol 151(8):1272–1279.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  126. 126.

    Rosemergy I, Adler J, Psirides A (2016) Cannabidiol oil in the treatment of super refractory status epilepticus. A case report. Seizure 35:56–58

    PubMed  Article  Google Scholar 

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The authors are supported by grants from the Department of Defense (CDMRP W81XWH-14-1-0558 to A.K.S.) and the Department of Veterans Affairs (VA Merit Award grant I01BX000883 and VA-BLR&D Research Career Scientist award, 1IK6BX003612 to A.K.S.). Olagide W Castro was supported by a Visiting Scientist Award from CAPES Foundation, Ministry of Education, Government of Brazil (O.W.C).

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Correspondence to Ashok K. Shetty.

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Upadhya, D., Castro, O.W., Upadhya, R. et al. Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities. Mol Neurobiol 55, 6956–6964 (2018).

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  • Cannabidiol
  • Cognitive dysfunction
  • Chronic epilepsy
  • Depression
  • Memory
  • Mossy fiber sprouting
  • Spontaneous seizures
  • Status epilepticus