Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity.

Erika Meyer,Marco Aurélio Mori,Rúbia Maria Weffort De Oliveira,Bianca Andretto Mattos,Francisco Silveira Guimarães,Alline Cristina De Campos,Jéssica Mendes Bonato,Humberto Milani

doi:10.1007/s12035-021-02479-7

Erika Meyer, Marco Aurélio Mori + Show 6 more

Open Access

https://doi.org/10.1007/s12035-021-02479-7

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Abstract

Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10mg/kg CBD (i.p.) 30min before surgery, 3h after surgery, and then once daily for 14days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.

Highlights

Transient global cerebral ischemia (TGCI) is a devastating outcome of reversible cardiac arrest and other clinical conditions, such as severe cardiac arrhythmias, respiratory arrest, gas poisoning, hypotensive shock, and perinatal asphyxia, which may result in hypoxic/ischemic brain damage [1, 2]
A main effect of trial was not detected for any of the three parameters (F1,36 = 0.74–1.62, p > 0.05), memory performance appeared to improve from RMT1 to RMT2 in the TGCI + vehicle group
These results indicate that TGCI caused persistent retrograde amnesia, despite some degree of improvement

Summary

Introduction

Transient global cerebral ischemia (TGCI) is a devastating outcome of reversible cardiac arrest and other clinical conditions, such as severe cardiac arrhythmias, respiratory arrest, gas poisoning, hypotensive shock, and perinatal asphyxia, which may result in hypoxic/ischemic brain damage [1, 2]. Hippocampal damage is associated with long-term sequelae of GCI, such as cognitive impairments, spatial/temporal disorientation, and deficits in learning, memory, and attention [9]. Pazos et al (2012) investigated the effects of CBD on cognition in newborn rats that were subjected to hypoxia/ischemia (HI)-induced brain injury. In mice with global GCI that was induced by bilateral common carotid artery occlusion (BCCAO), daily CBD treatment (3–30 mg/kg) for 14 days improved spatial memory in the Morris water maze [17]. Mice that were subjected to BCCAO and received short-term CBD treatment (10 mg/kg, 30 min before and 24, 48, and 72 h after BCCAO) performed better than sham controls in spatial memory tests (i.e., Y-maze test and object location test [OLT]) [18]

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