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).
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Abbreviations
- DMSO:
-
dimethyl sulfoxide
- WIN:
-
WIN 55,212-2
- PB:
-
phenobarbital
- P:
-
postnatal day
References
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
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
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
Bittigau P, Sifringer M, Ikonomidou C (2003) Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci 993:103–114 discussion 123-124
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
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
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
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
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
Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516. https://doi.org/10.1080/01926230701320337
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 48:443–450
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
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
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
Friedman D, Devinsky O (2015) Cannabinoids in the treatment of epilepsy. N Engl J Med 373:1048–1058. https://doi.org/10.1056/NEJMra1407304
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
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 26:501–507
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
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
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 78:1415–1427
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
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
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
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
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 261:1–4
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
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
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 283:70–74
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
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 23:876–882
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
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
Kubova H, Mares P (1991) Anticonvulsant effects of phenobarbital and primidone during ontogenesis in rats. Epilepsy Res 10:148–155
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
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
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 9:261–274
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
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
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
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
Ramachandra R, Subramanian T (2011) Atlas of the neonatal rat brain. CRC Press, Boca Raton
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
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
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 21:109–116
Sánchez AJ, García-Merino A (2012) Neuroprotective agents: cannabinoids. Clin Immunol 142:57–67. https://doi.org/10.1016/j.clim.2011.02.010
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
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 243:337–357
Shen M, Piser T, Seybold V, Thayer S (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16:4322–4334
Szabo B, Wallmichrath I, Mathonia P, Pfreundtner C (2000) Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 97:89–97
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
World Health Organization, Department of Mental Health and Substance Abuse, Agarwal R, et al (2011) Guidelines on neonatal seizures
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MNH was supported by TL1TR001431; PAF was supported by R01NS097762 and KL2TR001432.
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Huizenga, M.N., Forcelli, P.A. Neuroprotective Action of the CB1/2 Receptor Agonist, WIN 55,212-2, against DMSO but Not Phenobarbital-Induced Neurotoxicity in Immature Rats. Neurotox Res 35, 173–182 (2019). https://doi.org/10.1007/s12640-018-9944-9
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DOI: https://doi.org/10.1007/s12640-018-9944-9