Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia

Martı́nez-Orgado, José; Fernández-Frutos, Beatriz; González, Rita; Romero, Eva; Urigüen, Leyre; Romero, Julián; Viveros, María-Paz

doi:10.1016/s0169-328x(03)00163-3

Cited by 50 publications

(32 citation statements)

References 42 publications

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“…Coronal sections (4 m) were cut and mounted on a glass slide to be stained. To assess brain damage, consecutive pairs of brain sections were stained by two different methods (16): First, Nissl staining to determine early neuronal necrosis. Areas of 1 mm 2 in the central three lobes of the parietal cortex and in the CA1 area of hippocampus were examined using a light microscope (ϫ400) by an investigator blinded to the experimental group, using a grid of 50 compartments, calculating the mean of 5 compartments.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

Álvarez¹,

Lafuente²,

Rey-Santano³

et al. 2008

Pediatr Res

131

113

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ABSTRACT:To test the neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol (CBD), piglets received i.v. CBD or vehicle after hypoxia-ischemia (HI: temporary occlusion of both carotid arteries plus hypoxia). Nonhypoxic-ischemic sham-operated piglets remained as controls. Brain damage was studied by near-infrared spectroscopy (NIRS) and amplitudeintegrated electroencephalography (aEEG) and by histologic assessment (Nissl and FluoroJadeB staining). In HIϩvehicle, HI led to severe cerebral hemodynamic and metabolic impairment, as reflected in NIRS by an increase in total Hb index (THI) and a decrease in the fractional tissue oxygenation extraction (FTOE); in HIϩCBD the increase of THI was blunted and FTOE remained similar to SHAM. HI profoundly decreased EEG amplitude, which was not recovered in HIϩvehicle, indicating cerebral hypofunction; seizures were observed in all HIϩvehicle. In HIϩCBD, however, EEG amplitude recovered to 46.4 Ϯ 7.8% baseline and seizures appeared only in 4/8 piglets (both p Ͻ 0.05). The number of viable neurons decreased and that of degenerating neurons increased in HIϩvehicle; CBD reduced both effects by more than 50%. CBD administration was free from side effects; moreover, CBD administration was associated with cardiac, hemodynamic, and ventilatory beneficial effects. In conclusion, administration of CBD after HI reduced short-term brain damage and was associated with extracerebral benefits. (Pediatr Res 64: 653-658, 2008)

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Section: Methodsmentioning

confidence: 99%

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

Álvarez¹,

Lafuente²,

Rey-Santano³

et al. 2008

Pediatr Res

131

113

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“…P7 Wistar rat pups were used in all the experiments, which adhered to the guidelines of the Animal Welfare Committee of the Universidad Complutense of Madrid (following EU directives 86/609/CEE and 2003/65/CE). To induce HI brain damage, we followed the protocol we described previously (21), except that after left carotid artery ligature, pups were now exposed to 8% O 2 and 92% N 2 for 120 min to accomplish the Rice-Vannucci model (17). Three pups died during the HI procedure.…”

Section: Methodsmentioning

confidence: 99%

“…WIN and the corresponding antagonist were administered simultaneously. Doses were selected following previous studies from several groups including ours (16,21). Each experimental group con-tained pups from at least three different litters.…”

Section: Methodsmentioning

confidence: 99%

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The Cannabinoid Agonist Win55212 Reduces Brain Damage in an In Vivo Model of Hypoxic-Ischemic Encephalopathy in Newborn Rats

et al. 2007

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Neonatal hypoxic-ischemic encephalopathy (NHIE) is a devastating condition for which effective therapeutic treatments are still unavailable. Cannabinoids emerge as neuroprotective substances in adult animal studies; therefore, we aimed herein to test whether cannabinoids might reduce brain damage induced by hypoxiaischemia (HI) in newborn rats. Thus, 7-d-old Wistar rats (P7) were exposed to 8% O 2 for 120 min after left carotid artery ligature, then received s.c. vehicle (VEH) (HIϩVEH), the cannabinoid agonist WIN55212 (WIN) (0.1 mg/kg), or WIN with the CB 1 or CB 2 receptor antagonist SR141617 (SR1) (3 mg/kg) or SR141588 (SR2) (2 mg/kg). Brain damage was assessed by magnetic resonance imaging (MRI) at 1, 3, and 7 d after the insult. At the end of the experiment, MRI findings were corroborated by histology (Nissl staining). HIϩVEH showed an area of cytotoxic and vasogenic edema at 24 h after the insult, then evolving to necrosis. HIϩWIN showed a similar damaged area at 24 h after the insult, but the final necrotic area was reduced by 66%. Coadministration of either SR1 or SR2 reversed the effects of WIN. N HIE remains as a prevalent condition, inducing devastating brain injury leading to death or long-lasting sequelae (1,2). Despite recent progress in neonatology, the incidence of NHIE is not decreasing, likely because the complex pathophysiology of NHIE demands combined therapies or the use of treatments acting at different levels, as hypothermia (1,(3)(4)(5). In addition, due to the current inability to predict accurately perinatal asphyxia, only a posteriori treatments are feasible (1,2).Cannabinoids and their receptors constitute an endogenous system involved, for instance, in the control of synaptic transmission, memory modulation, motivation, movement, nociception, appetite, and thermoregulation (6,7). Two cannabinoid receptors present in the brain have been cloned so far: CB 1 receptors are expressed primarily by neurons but can also be found in glial cells; CB 1 receptors are Gi/o proteincoupled receptors that modulate the activity of several plasma membrane proteins and intracellular signaling pathways (7,8). CB 2 receptors are also Gi/o protein-coupled receptors; although it is accepted that CB 2 receptors are not expressed in forebrain neurons, they have been described in activated glia (8 -10). Lately, cannabinoids are emerging as valuable neuroprotective agents in models of acute and chronic neurodegenerative conditions (6,7,11-15), which may also affect the immature rat brain (16).Due to this evidence, we decided to test whether cannabinoids might be useful for decreasing brain damage in NHIE. For this purpose, we used the Rice-Vannucci model (17), an in vivo model that closely mimics actual NHIE conditions. Importantly, we assessed the effect of WIN when administered after the onset of the HI insult. To evaluate brain damage, we used MRI, an approach with several advantages: (1) MRI allows the development of imaging-based longitudinal studies, providing important data on the response tim...

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“…This evidence derives from studies that were initiated >10 years ago using newborn rat forebrain slices subjected to oxygen glucose deprivation and exposed to the CB 1 R/CB 2 R agonist WIN55212-2, which reduced cell death, decreasing glutamate and cytokine release, as well as inducible nitric oxide synthase expression, effects that were abolished by either CB 1 R or CB 2 R antagonists [65]. In newborn rats exposed to severe anoxia or to acute hypoxiaischemia [66,67], postinsult administration of WIN55212-2 afforded a strong neuroprotective effect, abolished by either CB 1 R or CB 2 R antagonists, too, as well as increasing neuronal and oligodendroglial cell proliferation in the subventricular zone 7 days after neonatal HI in rats [68]. In term fetal lambs exposed to HI damage by umbilical cord occlusion, postinsult administration of WIN55212-2 improved cerebral blood flow and reduced astrocytic, as well as apoptotic neuronal, death-those effects relying on the preservation of mitochondrial integrity and functionality [69].…”

Section: Cannabinoids and Brain Damage In The Immature Brain: Neonatamentioning

confidence: 99%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

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Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

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Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia

Cited by 50 publications

References 42 publications

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets

The Cannabinoid Agonist Win55212 Reduces Brain Damage in an In Vivo Model of Hypoxic-Ischemic Encephalopathy in Newborn Rats

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

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