Cannabidiol in experimental cerebral ischemia.

The absence of blood flow in cerebral ischemic conditions triggers a multitude of intricate pathophysiological mechanisms, including excitotoxicity, oxidative stress, neuroinflammation, disruption of the blood-brain barrier and white matter disarrangement. Despite numerous experimental studies conducted in preclinical settings, existing treatments for cerebral ischemia (CI), such as mechanical and pharmacological therapies, remain constrained and often entail significant side effects. Therefore, there is an imperative to explore innovative strategies for addressing CI outcomes.

Cannabidiol improves non-motor symptoms, attenuates neuroinflammation, and favours hippocampal newborn neuronal maturation in a rat model of Parkinsonism.

Objective: To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions.

Methods: Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioural paradigms to evaluate non-motor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis.

The chronic pharmacological antagonism of the CB receptor is not involved in the behavioral effects of antidepressants administered in mice submitted to chronic unpredictable stress.

Several pieces of evidence suggest that the monoaminergic theory of depression cannot fully explain all behavioral and neuroplastic changes observed after antidepressant chronic treatment. Other molecular targets, such as the endocannabinoid system, have been associated with the chronic effects of these drugs. In the present study, we hypothesized that the behavioral and neuroplastic effects observed after repeated treatment with the antidepressants (AD) Escitalopram (ESC) or venlafaxine (VFX) in chronically stressed mice depend on CB1 receptor activation.

Blood-Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats.

Phosphodiesterase 4 inhibitors (PDE4-I), which selectively increase cyclic adenosine monophosphate (cAMP) levels, have shown neuroprotective effects after several neurological injuries inducing blood-brain barrier (BBB) damage including local/focal cerebral ischemia. The present investigated whether roflumilast confers BBB neuroprotection in the hippocampus after transient global cerebral ischemia (TGCI) in rats. TGCI resulted in whole BBB disruption as measured by the increase of Evans blue (EB) and IgG extravasation, neurodegeneration, and downregulation of claudin-5 and endothelial nitric oxide synthase (eNOS) levels in the CA1 hippocampal subfield of ischemic rats.

NLX-101, a 5-HT receptor-biased agonist, improves pattern separation and stimulates neuroplasticity in aged rats.

5-HT serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT receptor-biased agonist, and F13714, a presynaptic 5-HT receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus.

Delayed administration of Trichilia catigua A. Juss. Ethyl-acetate fraction after cerebral ischemia prevents spatial memory deficits, decreases oxidative stress, and impacts neural plasticity in rats.

Ethnopharmacological Relevance: Trichilia catigua A. Juss (Meliaceae) is used in Brazilian folk medicine to alleviate fatigue and emotional stress and improve memory. Previous studies from our laboratory reported that an ethyl-acetate fraction (EAF) of T.

Long-term treatment with roflumilast improves learning of fear extinction memory and anxiety-like response in a type-1 diabetes mellitus animal model.

Diabetic encephalopathy is related to serious damage to the Central Nervous System leading to several disturbances in memory processing and emotions. It is known that the cyclic adenosine 3',5'-monophosphate (cAMP) responsive element-binding protein (CREB) pathway participates in neuronal plasticity and prevention of neuroinflammation, as well as the mediation of learning/memory processes and emotions in brain areas such as the hippocampus (HIP) and prefrontal cortex (PFC). We aimed to investigate the effect of acute (one injection) and long-term treatment (21 days) with roflumilast (ROF; i.

Cannabidiol Exerts a Neuroprotective and Glia-Balancing Effect in the Subacute Phase of Stroke.

Pharmacological agents limiting secondary tissue loss and improving functional outcomes after stroke are still limited. Cannabidiol (CBD), the major non-psychoactive component of , has been proposed as a neuroprotective agent against experimental cerebral ischemia. The effects of CBD mostly relate to the modulation of neuroinflammation, including glial activation.

Spontaneous Activity of CB Receptors Attenuates Stress-Induced Behavioral and Neuroplastic Deficits in Male Mice.

The monoaminergic theory of depression/anxiety disorders cannot fully explain the behavioral and neuroplastic changes observed after ADs chronic treatment. Endocannabinoid system, which comprises CB2 receptors, has been associated with the chronic effects of these drugs, especially in stressed mice. CB2-KO mice display more vulnerability to stressful stimuli.

Positive effects of roflumilast on behavior, neuroinflammation, and white matter injury in mice with global cerebral ischemia.

Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro.

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

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.

Involvement of dopamine D and glutamate NMDA receptors in the antidepressant-like effect of amantadine in mice.

The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time.

Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue.

Ischemic stroke is caused by a thromboembolic occlusion of a major cerebral artery, with the impaired blood flow triggering neuroinflammation and subsequent neuronal damage. Both the innate immune system (e.g.

Persistence of the extinction of fear memory requires late-phase cAMP/PKA signaling in the infralimbic cortex.

Fear extinction is a form of new learning that inhibits expression of the original fear memory without erasing the conditioned stimulus-unconditioned stimulus association. Much is known about the mechanisms that underlie the acquisition of extinction, but the way in which fear extinction is maintained has been scarcely explored. Evidence suggests that protein kinase A (PKA) in the frontal cortex might be related to the persistence of extinction.

Postischemic fish oil treatment restores dendritic integrity and synaptic proteins levels after transient, global cerebral ischemia in rats.

We previously found that fish oil (FO) facilitated memory recovery in the absence of pyramidal neuron rescue after transient, global cerebral ischemia (TGCI). Fish oil preserved the expression of microtubule-associated protein 2 (MAP-2), suggesting a relationship between dendritic plasticity and memory recovery that is mediated by FO after TGCI. The present study examined whether postischemic treatment with FO prevents ischemia-induced loss of dendritic processes in remaining pyramidal neurons.

Ethyl-acetate fraction of Trichilia catigua protects against oxidative stress and neuroinflammation after cerebral ischemia/reperfusion.

Ethnopharmacological Relevance: Trichilia catigua A. Juss (Meliaceae) preparations have been used in folk medicine to alleviate fatigue, stress, and improve memory. Antinociceptive, antiinflammatory, and in vitro neuroprotective effects have been observed in animals.

Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson's disease in rats.

Deficiencies in adult hippocampal neurogenesis have been suggested to be a possible pathophysiological mechanism that underlies depressive symptoms that are often observed in patients with Parkinson's disease (PD). Pioglitazone, a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, has been shown to exert antiinflammatory and antidepressant effects and modulate neural plasticity in several neurodegenerative disorders. The present study investigated the effects of pioglitazone on depressive phenotypes and adult hippocampal neurogenesis in a rat model of PD that was induced by bilateral 6-hydroxydopamine (6-OHDA) infusions in the substantia nigra pars compact (SNpc).

Ethyl-acetate fraction of Trichilia catigua restores long-term retrograde memory and reduces oxidative stress and inflammation after global cerebral ischemia in rats.

We originally reported that an ethyl-acetate fraction (EAF) of Trichilia catigua prevented the impairment of water maze learning and hippocampal neurodegeneration after transient global cerebral (TGCI) in mice. We extended that previous study by evaluating whether T. catigua (i) prevents the loss of long-term retrograde memory assessed in the aversive radial maze (AvRM), (ii) confers hippocampal and cortical neuroprotection, and (iii) mitigates oxidative stress and neuroinflammation in rats that are subjected to the four vessel occlusion (4-VO) model of TGCI.

Depletion of 5 hydroxy-triptamine (5-HT) affects the antidepressant-like effect of neuronal nitric oxide synthase inhibitor in mice.

Clinical and experimental evidence indicates that nitric oxide (NO) is involved in the genesis of depression as well as in antidepressant drug effects. Inhibitors of nitric oxide synthases (NOS) exert antidepressant-like effect in several animal models, but also interfere with the locomotor activity. The involvement of different isoforms of NOS in the antidepressant-like effects is not clearly established.

Postischemic fish oil treatment confers task-dependent memory recovery.

A series of our previous studies demonstrated that fish oil (FO), equivalent to 300mg/kg docosahexahenoic acid (DHA), facilitates memory recovery after transient, global cerebral ischemia (TGCI) in the aversive radial maze (AvRM). The present study sought to address two main issues: (i) whether the memory-protective effect of FO that has been observed in the AvRM can be replicated in the passive avoidance test (PAT) and object location test (OLT) and (ii) whether FO at doses that are lower than those used previously can also prevent TGCI-induced memory loss. In Experiment 1, naive rats were trained in the PAT, subjected to TGCI (4-vessel occlusion model), and tested for retrograde memory performance 8 and 15days after ischemia.

Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia.

This study investigated the effects of cannabidiol (CBD), a non-psychotomimetic phytochemical present in Cannabis sativa, on the cognitive and emotional impairments induced by bilateral common carotid artery occlusion (BCCAO) in mice. Using a multi-tiered behavioral testing battery during 21days, we found that BCCAO mice exhibited long-lasting functional deficits reflected by increase in anxiety-like behavior (day 9), memory impairments (days 12-18) and despair-like behavior (day 21). Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO.

The phosphodiesterase type 2 inhibitor BAY 60-7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity.

Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60-7550, a selective phosphodiesterase type 2 inhibitor (PDE2-I), presents memory-enhancing and anxiolytic-like properties. The behavioral effects of BAY 60-7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity.

Myricitrin induces antidepressant-like effects and facilitates adult neurogenesis in mice.

Myricitrin (MYR) is a natural flavonoid that inhibits nitric oxide (NO) transmission and has an atypical antipsychotic-like profile in animal models. Considering that several NO inhibitors exert antidepressant-like effects, the present study evaluated the antidepressant-like effect of MYR (3-30mg/kg) in the tail suspension test (TST). Because of the putative relationship between adult neurogenesis and antidepressant activity, we also assessed cell proliferation, survival, and differentiation in adult neurogenic niches, including the subgranular zone (SGZ) and subventricular zone (SVZ).

Postischemic fish oil treatment restores long-term retrograde memory and dendritic density: An analysis of the time window of efficacy.

We reported that fish oil (FO) prevented the loss of spatial memory caused by transient, global cerebral ischemia (TGCI), provided the treatment covered the first days prior to and after ischemia. Continuing these studies, trained rats were subjected to TGCI, and FO was administered for 10days, with a time window of efficacy (TWE) of 4, 8 or 12h post-ischemia. Retrograde memory was assessed up to 43days after TGCI.