Hypoxic-ischemic encephalopathy

Hypoxic-ischemic encephalopathy is a form of brain injury caused by oxygen deprivation during the birth process. It can cause sensorimotor and cognitive impairments including physical and intellectual disability. The endocannabinoid system can regulate the underlying processes of Hypoxic-ischemic encephalopathy when its occurring, therefore cannabinoids could help to ameliorate the symptoms related to it.

Alternative Names: 
Perinatal asphyxia <br> <br>Intrauterine hypoxia
Literature Discussion: 

The endocannabinoid system plays a role in neonatal Hypoxic-ischemic encephalopathy.

cannabinoid receptors CB1 and CB2 are upregulated and endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England et al., 2015; Lara-Celador et al., 2013).

These increased levels of endocannabinoids would reduce apoptotic cell death and reduce brain injury (Lara-Celador et al., 2012).

The endocannabinoid system would be involved in the reduction of glutamate excitotoxicity, neuroinflammation and oxidative stress (Booz, 2011; Capettini et al., 2012; Fernández-López et al., 2013).

AEA modulates the function of the glia increasing its pro-inflammatory response in the brain (Vázquez et al., 2015).

Selective activation of CB1 reduces astrocytic reaction, neuronal death and dendritic loss in a stoke model in adult mice (Caltana et al., 2015).

Selective activation of CB2 reduces neuroinflammation, ischemic injury and cognitive deficits in different models of Stroke, probably through modulation of AMPK/CREB signaling (Choi et al., 2013; Ronca et al., 2015; Zarruk et al., 2012).

Activation of CB1 and CB2 through synthetic cannabinoid WIN 55,212-2 in different hypoxia-ischemic newborn animal models showed neuroprotective effects, decreased brain injury and reduced apoptotic cell death by acting on glutamatergic excitotoxicity, TNF-alpha release, and iNOS expression (Alonso-AlcoNADA et al., 2010, 2012; Fernández-López et al., 2006, 2007, 2010; Martínez-Orgado et al., 2003).

Activation of PPAR-γ receptor showed behavioral recovery and microglial supression in a model of Stroke (Yu et al., 2015).

CBD showed neuroprotective effects with functional and behavioral recovery in hypoxia-ischemic animal models (Alvarez et al., 2008; Lafuente et al., 2011).

CBD increased neuronal and astrocyte survival and reduced brain damage and reactive astrogliosis (Hayakawa et al., 2009; Schiavon et al., 2014).

CBD mechanisms would involve the modulation of excitotoxicity, oxidative stress and inflammation through CB2, 5HT1A, Adenosine A2A and PPAR-γ receptors (Castillo et al., 2010; Hind et al., 2015; Pazos et al., 2012, 2013).

CBD shows neuroprotective effects in a rat model of HI in a wider time window than any other neuroprotective treatment for this pathology (Mohammed, Ceprián, Jimenez, Pazos, & Martínez-Orgado, 2016).

Similar to previous studies in HI, rat models of Arterial Isquemic Stroke showed improved neurobehavioral functioning after CBD treatment, including modulation of astrogliosos and microglial proliferation while showed reduced excitotocicity, neuronal loss and apoptosis (Ceprián et al., 2016).

CBD, combined with hypotermia (typical treatment for HI), improves effects of exitotoxicity, inflammation, oxidative stress and cell damage compared to the treatment of hypothermia or cannabidiol alone (Lafuente et al., 2016).

For more information about cannabinoids in hypoxia-ischemic brain injury and Stroke see Alonso-AlcoNADA (2011) and Fernández-Ruiz (2015).


Alonso-AlcoNADA, D., Alvarez, F.J., Alvarez, A., Mielgo, V.E., Goñi-de-Cerio, F., Rey-Santano, M.C., Caballero, A., Martinez-Orgado, J., and Hilario, E. (2010). The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic-ischemic injury in fetal lambs. Brain Res. 1362, 150–159.

Alonso-AlcoNADA, D., Alvarez, A., and Hilario, E. (2011). cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury. Neurosci. Bull. 27, 275–285.

Alonso-AlcoNADA, D., Alvarez, A., Alvarez, F.J., Martínez-Orgado, J.A., and Hilario, E. (2012). The cannabinoid WIN 55212-2 mitigates apoptosis and mitochondrial dysfunction after hypoxia ischemia. Neurochem. Res. 37, 161–170.

Alvarez, F.J., Lafuente, H., Rey-Santano, M.C., Mielgo, V.E., Gastiasoro, E., Rueda, M., Pertwee, R.G., Castillo, A.I., Romero, J., and Martínez-Orgado, J. (2008). Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr. Res. 64, 653–658.

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

Caltana, L., Saez, T.M., Aronne, M.P., and Brusco, A. (2015). cannabinoid receptor type 1 agonist ACEA improves motor recovery and protects neurons in ischemic Stroke in mice. J. Neurochem. 135, 616–629.

Capettini, L.S.A., Savergnini, S.Q., da Silva, R.F., Stergiopulos, N., Santos, R.A.S., Mach, F., and Montecucco, F. (2012). Update on the Role of cannabinoid Receptors after Ischemic Stroke. Mediators Inflamm. 2012.

Castillo, A., Tolón, M.R., Fernández-Ruiz, J., Romero, J., and 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, 434–440.

Ceprián, M., Jiménez-Sánchez, L., Vargas, C., Barata, L., Hind, W., & Martínez-Orgado, J. (2016). Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic Stroke. Neuropharmacology, 116, 151-159. https://doi.org/10.1016/j.neuropharm.2016.12.017

Choi, I.-Y., Ju, C., Anthony Jalin, A.M.A., Lee, D.I., Prather, P.L., and Kim, W.-K. (2013). Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am. J. Pathol. 182, 928–939.

England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental Stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.

Fernández-López, D., Martínez-Orgado, J., Nuñez, E., Romero, J., Lorenzo, P., Moro, M.A., and Lizasoain, I. (2006). Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr. Res. 60, 169–173.

Fernández-López, D., Pazos, M.R., Tolón, R.M., Moro, M.A., Romero, J., Lizasoain, I., and Martínez-Orgado, J. (2007). The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of Hypoxic-ischemic encephalopathy in newborn rats. Pediatr. Res. 62, 255–260.

Fernández-López, D., Pradillo, J.M., García-Yébenes, I., Martínez-Orgado, J.A., Moro, M.A., and Lizasoain, I. (2010). The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia. Stroke J. Cereb. Circ. 41, 2956–2964.

Fernández-López, D., Lizasoain, I., Moro, M.Á., and Martínez-Orgado, J. (2013). cannabinoids: Well-Suited Candidates for the Treatment of Perinatal Brain Injury. Brain Sci. 3, 1043–1059.

Fernández-Ruiz, J., Moro, M.A., and Martínez-Orgado, J. (2015). cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications. Neurotherapeutics 12, 793–806.

Hayakawa, K., Irie, K., Sano, K., Watanabe, T., Higuchi, S., Enoki, M., Nakano, T., Harada, K., Ishikane, S., Ikeda, T., et al. (2009). Therapeutic time window of cannabidiol treatment on delayed ischemic damage via high-mobility group box1-inhibiting mechanism. Biol. Pharm. Bull. 32, 1538–1544.

Hind, W.H., England, T.J., and O’Sullivan, S.E. (2015). Cannabidiol protects an in vitro model of the blood brain barrier (BBB) from oxygen-glucose deprivation via PPARγ and 5-HT1A. Br. J. Pharmacol.

Lafuente, H., Alvarez, F.J., Pazos, M.R., Alvarez, A., Rey-Santano, M.C., Mielgo, V., Murgia-Esteve, X., Hilario, E., and Martinez-Orgado, J. (2011). Cannabidiol Reduces Brain Damage and Improves Functional Recovery After Acute Hypoxia-Ischemia in Newborn Pigs. Pediatr. Res. 70, 272–277.

Lafuente, H., Pazos, M. R., Alvarez, A., Mohammed, N., Santos, M., Arizti, M., … Martinez-Orgado, J. A. (2016). Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia. Frontiers in Neuroscience, 10, 323. https://doi.org/10.3389/fnins.2016.00323

Lara-Celador, I., Castro-Ortega, L., Alvarez, A., Goñi-de-Cerio, F., Lacalle, J., and Hilario, E. (2012). endocannabinoids reduce cerebral damage after hypoxic-ischemic injury in perinatal rats. Brain Res. 1474, 91–99.

Lara-Celador, I., Goñi-de-Cerio, F., Alvarez, A., and Hilario, E. (2013). Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury. Neural Regen. Res. 8, 731–744.

Martínez-Orgado, J., Fernández-Frutos, B., González, R., Romero, E., Urigüen, L., Romero, J., and Viveros, M.P. (2003). Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia. Brain Res. Mol. Brain Res. 114, 132–139.

Mohammed, N., Ceprián, M., Jimenez, L., Pazos, M. R., & Martínez-Orgado, J. (2016). Neuroprotective Effects of Cannabidiol In Hypoxic Ischemic Insult: The Therapeutic Window In Newborn Mice. CNS & Neurological Disorders Drug Targets.

Pazos, M.R., Cinquina, V., Gómez, A., Layunta, R., Santos, M., Fernández-Ruiz, J., and Martínez-Orgado, J. (2012). Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology 63, 776–783.

Pazos, M.R., Mohammed, N., Lafuente, H., Santos, M., Martínez-Pinilla, E., Moreno, E., Valdizan, E., Romero, J., Pazos, A., Franco, R., et al. (2013). Mechanisms of cannabidiol neuroprotection in hypoxic–ischemic newborn pigs: Role of 5HT1A and CB2 receptors. Neuropharmacology 71, 282–291.

Ronca, R.D., Myers, A.M., Ganea, D., Tuma, R.F., Walker, E.A., and Ward, S.J. (2015). A selective cannabinoid CB2 agonist attenuates damage and improves memory retention following Stroke in mice. Life Sci. 138, 72–77.

Schiavon, A.P., Soares, L.M., Bonato, J.M., Milani, H., Guimarães, F.S., and Weffort de Oliveira, R.M. (2014). Protective effects of cannabidiol against hippocampal cell death and cognitive impairment induced by bilateral common carotid artery occlusion in mice. Neurotox. Res. 26, 307–316.

Vázquez, C., Tolón, R. M., Pazos, M. R., Moreno, M., Koester, E. C., Cravatt, B. F., … Romero, J. (2015). endocannabinoids regulate the activity of astrocytic hemichannels and the microglial response against an injury: In vivo studies. Neurobiology of Disease, 79, 41-50. https://doi.org/10.1016/j.nbd.2015.04.005

Yu, S.-J., Reiner, D., Shen, H., Wu, K.-J., Liu, Q.-R., and Wang, Y. (2015). Time-Dependent Protection of CB2 Receptor Agonist in Stroke. PloS One 10, e0132487.

Zarruk, J.G., Fernández-López, D., García-Yébenes, I., García-Gutiérrez, M.S., Vivancos, J., Nombela, F., Torres, M., Burguete, M.C., Manzanares, J., Lizasoain, I., et al. (2012). cannabinoid type 2 receptor activation downregulates Stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke J. Cereb. Circ. 43, 211–219. 

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