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Neurotoxicity Research

, Volume 35, Issue 1, pp 173–182 | Cite as

Neuroprotective Action of the CB1/2 Receptor Agonist, WIN 55,212-2, against DMSO but Not Phenobarbital-Induced Neurotoxicity in Immature Rats

  • Megan N. Huizenga
  • Patrick A. ForcelliEmail author
ORIGINAL ARTICLE
  • 93 Downloads

Abstract

The developing brain is uniquely susceptible to drug-induced increases in programmed cell death or apoptosis. Many compounds, including anticonvulsant drugs, anesthetic agents, and ethanol, when administered in a narrow postnatal window in rodents, result in increased pruning of neurons. Here, we report that dimethyl sulfoxide (DMSO) triggers widespread neurodegeneration in the immature (postnatal day, P7) rat brain, an effect consistent with a prior report in neonatal mice. We found that the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) exerts a neuroprotective effect against DMSO-induced cell death. We extended these findings to determine if WIN is neuroprotective against another drug class known to increase developmental cell death, namely antiseizure drugs. The antiseizure drug phenobarbital (PB) remains the primary treatment for neonatal seizures, despite significantly increasing cell death in the developing rodent brain. WIN exerts antiseizure effects in immature rodent seizure models, but increases the toxicity associated with neonatal ethanol exposure. We thus sought to determine if WIN would protect against or exacerbate PB-induced cell death. Unlike either the prior report with ethanol or our present findings with DMSO, WIN was largely without effect on PB-induced cell death. WIN alone did not increase cell death over levels observed in vehicle-treated rats. These data suggest that WIN has a favorable safety profile in the developing brain and could potentially serve as an adjunct therapy with phenobarbital (albeit one that does not attenuate PB-induced toxicity).

Keywords

Apoptosis Cell death Degeneration Development Rat Toxicity Brain growth spurt Barbiturate Cannabinoid 

Abbreviations

DMSO

dimethyl sulfoxide

WIN

WIN 55,212-2

PB

phenobarbital

P

postnatal day

Notes

Funding

MNH was supported by TL1TR001431; PAF was supported by R01NS097762 and KL2TR001432.

References

  1. Bardutzky J, Meng X, Bouley J, Duong T, Ratan R et al (2005) Effects of intravenous dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model. J Cereb Blood Flow Metab 25:968–977.  https://doi.org/10.1038/sj.jcbfm.9600095 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bisogno T, Oddi S, Piccoli A, Domenico F, Maccarrone M (2016) Type-2 cannabinoid receptors in neurodegeneration. Pharmacol Res 111:721–730.  https://doi.org/10.1016/j.phrs.2016.07.021 CrossRefPubMedGoogle Scholar
  3. Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, Dzietko M, Pesditschek S, Mai I, Dikranian K, Olney JW, Ikonomidou C (2002) Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci 99:15089–15094.  https://doi.org/10.1073/pnas.222550499 CrossRefPubMedGoogle Scholar
  4. Bittigau P, Sifringer M, Ikonomidou C (2003) Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci 993:103–114 discussion 123-124CrossRefGoogle Scholar
  5. Bittigau P, Sifringer M, Ikonomidou C (2006) Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci 993:103–114.  https://doi.org/10.1111/j.1749-6632.2003.tb07517.x CrossRefGoogle Scholar
  6. Brown L, Gutherz S, Kulick C, Soper C, Kondratyev A, Forcelli PA (2016) Profile of retigabine-induced neuronal apoptosis in the developing rat brain. Epilepsia 57:660–670.  https://doi.org/10.1111/epi.13335 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Concannon R, Okine B, Finn D, Dowd E (2015) Differential upregulation of the cannabinoid CB2 receptor in neurotoxic and inflammation-driven rat models of Parkinson’s disease. Exp Neurol 269:133–141.  https://doi.org/10.1016/j.expneurol.2015.04.007
  8. De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T et al (2011) Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163:1479–1494.  https://doi.org/10.1111/j.1476-5381.2010.01166.x CrossRefPubMedPubMedCentralGoogle Scholar
  9. Dikranian K, Ishimaru M, Tenkova T, Labruyere J, Qin YQ et al (2001) Apoptosis in the in vivo mammalian forebrain. Neurobiol Dis 8:359–379.  https://doi.org/10.1006/nbdi.2001.0411 CrossRefPubMedGoogle Scholar
  10. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516.  https://doi.org/10.1080/01926230701320337 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Felder C, Joyce K, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 48:443–450PubMedGoogle Scholar
  12. Ferrer I, Soriano E, Del Rio J, Alcántara S, Auladell C et al (1992) Cell death and removal in the cerebral cortex during development. Prog Neurobiol 39:1–43.  https://doi.org/10.1016/0301-0082(92)90029-E CrossRefPubMedGoogle Scholar
  13. Forcelli P, Kim J, Kondratyev A, Gale K (2011) Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia 52:e207–e211.  https://doi.org/10.1111/j.1528-1167.2011.03297.x CrossRefPubMedPubMedCentralGoogle Scholar
  14. Forcelli P, Soper C, Duckles A, Gale K, Kondratyev A (2013) Melatonin potentiates the anticonvulsant action of phenobarbital in neonatal rats. Epilepsy Res 107:217–223.  https://doi.org/10.1016/j.eplepsyres.2013.09.013 CrossRefPubMedGoogle Scholar
  15. Friedman D, Devinsky O (2015) Cannabinoids in the treatment of epilepsy. N Engl J Med 373:1048–1058.  https://doi.org/10.1056/NEJMra1407304 CrossRefPubMedGoogle Scholar
  16. Gerdeman G, Lovinger D (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol 85:468–471.  https://doi.org/10.1152/jn.2001.85.1.468 CrossRefPubMedGoogle Scholar
  17. Giorgio D, M A, Hou Y, Zhao X, Zhang B et al (2008) Dimethyl sulfoxide provides neuroprotection in a traumatic brain injury model. Restor Neurol Neurosci 26:501–507Google Scholar
  18. Gowran A, Noonan J, Campbell VA (2011) The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther 17:637–644.  https://doi.org/10.1111/j.1755-5949.2010.00195.x CrossRefPubMedGoogle Scholar
  19. Hansen H, Krutz B, Sifringer M, Stefovska V, Bittigau P et al (2008) Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity. Ann Neurol 64:42–52.  https://doi.org/10.1002/ana.21287 CrossRefPubMedGoogle Scholar
  20. Hansen H, Schmid P, Bittigau P, Lastres-Becker I, Berrendero F et al (2001) Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J Neurochem 78:1415–1427CrossRefGoogle Scholar
  21. Hanslick JL, Lau K, Noguchi K, Olney J, Zorumski C et al (2009) Dimethyl sulfoxide (DMSO) produces widespread apoptosis in the developing central nervous system. Neurobiol Dis 34:1–10.  https://doi.org/10.1016/j.nbd.2008.11.006 CrossRefPubMedGoogle Scholar
  22. Harkany T, Guzmán M, Galve-Roperh I, Berghuis P, Devi L et al (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92.  https://doi.org/10.1016/j.tips.2006.12.004 CrossRefPubMedGoogle Scholar
  23. Heck N, Golbs A, Riedemann T, Sun J, Lessmann V et al (2008) Activity-dependent regulation of neuronal apoptosis in neonatal mouse cerebral cortex. Cereb Cortex 18:1335–1349.  https://doi.org/10.1093/cercor/bhm165 CrossRefPubMedGoogle Scholar
  24. Huizenga M, Wicker E, Beck V, Forcelli P (2017) Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats. Epilepsia 58:1593–1602.  https://doi.org/10.1111/epi.13842 CrossRefPubMedGoogle Scholar
  25. Hülsmann S, Greiner C, Köhling R, Wölfer J, Moskopp D, Riemann B, Lücke A, Wassmann H, Speckmann EJ (1999) Dimethyl sulfoxide increases latency of anoxic terminal negativity in hippocampal slices of guinea pig in vitro. Neurosci Lett 261:1–4CrossRefGoogle Scholar
  26. Ikonomidou C (2009) Triggers of apoptosis in the immature brain. Brain Dev 31:488–492.  https://doi.org/10.1016/j.braindev.2009.02.006 CrossRefPubMedGoogle Scholar
  27. Ikonomidou C, Bittigau P, Ishimaru M, Wozniak D, Koch C, Genz K, Price MT, Stefovska V, Hörster F, Tenkova T, Dikranian K, Olney JW (2000) Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287:1056–1060.  https://doi.org/10.1126/science.287.5455.1056 CrossRefPubMedGoogle Scholar
  28. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74CrossRefGoogle Scholar
  29. Jacob S, de la Torre J (2009) Pharmacology of dimethyl sulfoxide in cardiac and CNS damage. Pharmacol Rep 61:225–235.  https://doi.org/10.1016/S1734-1140(09)70026-X CrossRefPubMedGoogle Scholar
  30. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff N, Dikranian K et al (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882CrossRefGoogle Scholar
  31. Kaushal S, Tamer Z, Opoku F, Forcelli P (2016) Anticonvulsant drug-induced cell death in the developing white matter of the rodent brain. Epilepsia 57:727–734.  https://doi.org/10.1111/epi.13365 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kim J, Kondratyev A, Gale K (2007) Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther 323:165–173.  https://doi.org/10.1124/jpet.107.126250 CrossRefPubMedGoogle Scholar
  33. Kubova H, Mares P (1991) Anticonvulsant effects of phenobarbital and primidone during ontogenesis in rats. Epilepsy Res 10:148–155CrossRefGoogle Scholar
  34. Lu C, Mattson M (2001) Dimethyl sulfoxide suppresses NMDA- and AMPA-induced ion currents and calcium influx and protects against excitotoxic death in hippocampal neurons. Exp Neurol 170:180–185.  https://doi.org/10.1006/exnr.2001.7686 CrossRefPubMedGoogle Scholar
  35. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, van der Stelt M, López-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88.  https://doi.org/10.1126/science.1088208 CrossRefPubMedGoogle Scholar
  36. Maya-López M, Colín-González A, Aguilera G, de Lima M, Colpo-Ceolin A, Rangel-López E, Villeda-Hernández J, Rembao-Bojórquez D, Túnez I, Luna-López A, Lazzarini-Lechuga R, González-Puertos VY, Posadas-Rodríguez P, Silva-Palacios A, Königsberg M, Santamaría A (2017) Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors. Am J Transl Res 9:261–274PubMedPubMedCentralGoogle Scholar
  37. Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47.  https://doi.org/10.1146/annurev-psych-113011-143739 CrossRefPubMedGoogle Scholar
  38. Olney J, Wozniak D, Jevtovic-Todorovic V, Farber N, Bittigau P et al (2002) Drug-induced apoptotic neurodegeneration in the developing brain. Brain Pathol 12:488–498.  https://doi.org/10.1111/j.1750-3639.2002.tb00467.x CrossRefPubMedGoogle Scholar
  39. Olney J, Young C, Wozniak D, Jevtovic-Todorovic V, Ikonomidou C (2004) Do pediatric drugs cause developing neurons to commit suicide? Trends Pharmacol Sci 25:135–139.  https://doi.org/10.1016/j.tips.2004.01.002 CrossRefPubMedGoogle Scholar
  40. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215.  https://doi.org/10.1038/sj.bjp.0707442 CrossRefPubMedGoogle Scholar
  41. Ramachandra R, Subramanian T (2011) Atlas of the neonatal rat brain. CRC Press, Boca RatonCrossRefGoogle Scholar
  42. Ramírez BG, Blázquez C, Gómez del Pulgar T, Guzmán M, de Ceballos M (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913.  https://doi.org/10.1523/JNEUROSCI.4540-04.2005 CrossRefPubMedGoogle Scholar
  43. Rangel-López E, Colín-González A, Paz-Loyola A, Pinzón E, Torres I et al (2015) Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain. Neuroscience 285:97–106.  https://doi.org/10.1016/j.neuroscience.2014.11.016 CrossRefPubMedGoogle Scholar
  44. Robbe D, Alonso G, Duchamp F, Bockaert J, Manzoni O (2001) Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J Neurosci 21:109–116CrossRefGoogle Scholar
  45. Sánchez AJ, García-Merino A (2012) Neuroprotective agents: cannabinoids. Clin Immunol 142:57–67.  https://doi.org/10.1016/j.clim.2011.02.010 CrossRefPubMedGoogle Scholar
  46. Sánchez-Blázquez P, Rodríguez-Muñoz M, Vicente-Sánchez A, Garzón J (2013) Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate. Antioxid Redox Signal 19:1766–1782.  https://doi.org/10.1089/ars.2012.5100 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Sawada M, Sato M (1975) The effect of dimethyl sulfoxide on the neuronal excitability and cholinergic transmission in Aplysia ganglion cells. Ann N Y Acad Sci 243:337–357CrossRefGoogle Scholar
  48. Shen M, Piser T, Seybold V, Thayer S (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16:4322–4334CrossRefGoogle Scholar
  49. Szabo B, Wallmichrath I, Mathonia P, Pfreundtner C (2000) Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 97:89–97CrossRefGoogle Scholar
  50. Vicente-Sánchez A, Sánchez-Blázquez P, Rodríguez-Muñoz M, Garzón J (2013) HINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate glutamate NMDA receptor activity. Mol Brain 6:42.  https://doi.org/10.1186/1756-6606-6-42 CrossRefPubMedPubMedCentralGoogle Scholar
  51. World Health Organization, Department of Mental Health and Substance Abuse, Agarwal R, et al (2011) Guidelines on neonatal seizuresGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Pharmacology and PhysiologyGeorgetown UniversityWashingtonUSA
  2. 2.Department of NeuroscienceGeorgetown UniversityWashingtonUSA
  3. 3.Interdisciplinary Program in NeuroscienceGeorgetown UniversityWashingtonUSA

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