Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Behav Pharmacol ; 35(1): 26-35, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38085651

ABSTRACT

Chronic exposure to cocaine is known to have profound effects on the brain, leading to the dysregulation of inflammatory signalling pathways, the activation of microglia, and the manifestation of cognitive and motivational behavioural impairments. The endocannabinoid system has emerged as a potential mediator of cocaine's deleterious effects. In this study, we sought to investigate the therapeutic potential of the cannabinoid CB2 receptor agonist, JWH-133, in mitigating cocaine-induced inflammation and associated motivational behavioural alterations in an in vivo model. Our research uncovered compelling evidence that JWH-133, a selective CB2 receptor agonist, exerts a significant dampening effect on the reinstatement of cocaine-induced conditioned place preference. This effect was accompanied by notable changes in the neurobiological landscape. Specifically, JWH-133 administration was found to upregulate Δ-FOSB expression in the nucleus accumbens (Nac), elevate CX3CL1 levels in both the ventral tegmental area and prefrontal cortex (PFC), and concurrently reduce IL-1ß expression in the PFC and NAc among cocaine-treated animals. These findings highlight the modulatory role of CB2 cannabinoid receptor activation in altering the reward-seeking behaviour induced by cocaine. Moreover, they shed light on the intricate interplay between the endocannabinoid system and cocaine-induced neurobiological changes, paving the way for potential therapeutic interventions targeting CB2 receptors in the context of cocaine addiction and associated behavioural deficits.


Subject(s)
Cannabinoids , Cocaine , Mice , Animals , Endocannabinoids/metabolism , Receptor, Cannabinoid, CB2 , Cocaine/pharmacology , Cocaine/metabolism , Cannabinoids/pharmacology , Nucleus Accumbens/metabolism , Cannabinoid Receptor Agonists/pharmacology
2.
Neurotox Res ; 41(6): 615-626, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37782433

ABSTRACT

Cerebral metabolic abnormalities are common in neurodegenerative diseases. Previous studies have shown that mitochondrial damage alters ATP production and increases reactive oxygen species (ROS) release which may contribute to neurodegeneration. In the present study, we investigated the neuroprotective effects of cannabidiol (CBD), a non-psychoactive component derived from marijuana (Cannabis sativa L.), on astrocytic bioenergetic balance in a primary cell culture model of lipopolysaccharide (LPS)-induced neurotoxicity. Astrocytic metabolic profiling using an extracellular flux analyzer demonstrated that CBD decreases mitochondrial proton leak, increased spare respiratory capacity and coupling efficiency in LPS-stimulated astrocytes. Simultaneously, CBD increased astrocytic glycolytic capacity and glycolysis reserve in a cannabinoid receptor type 1 (CB1)-dependent manner. CBD-restored metabolic changes were correlated with a significant decrease in the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) concentration and reduction of ROS production in LPS-stimulated astrocytes. These results suggest that CBD may inhibit LPS-induced metabolic impairments and inflammation by enhancing astrocytic metabolic glycolysis versus oxidative phosphorylation through its action on CB1 receptors. The present findings suggest CBD as a potential anti-inflammatory treatment in metabolic pathologies and highlight a possible role for the cannabinoidergic system in the modulation of mitochondrial oxidative stress. CBD enhances mitochondrial bioenergetic profile, attenuates proinflammatory cytokines release, and ROS overproduction of astrocytes stimulated by LPS. These effects are not mediated directly by CB1 receptors, while these receptors seem to have a key role in the anti-inflammatory response of the endocannabinoid system on astrocytes, as their specific inhibition by SR141716A led to increased pro-inflammatory cytokines release and ROS production. The graphical abstract is created with BioRender.com.


Subject(s)
Cannabidiol , Cannabidiol/pharmacology , Lipopolysaccharides/toxicity , Receptors, Cannabinoid/metabolism , Reactive Oxygen Species/metabolism , Astrocytes , Cytokines , Anti-Inflammatory Agents/pharmacology
3.
Pharmacol Biochem Behav ; 211: 173290, 2021 12.
Article in English | MEDLINE | ID: mdl-34662589

ABSTRACT

Alcohol abuse is a widespread cause of aggressive and impulsive behaviors that impact the users as well as their entourage. However, only a few medications are effective. Recently, cannabidiol has been reported to improve mood disorders and recovery from substance abuse, yet the psychopharmacologic effects of cannabidiol in ethanol-induced drug reward and aggressivity remain unexplored. In the present study, we investigated the effects of cannabidiol on ethanol-induced place preference and aggressivity in individually and group-housed male rats using the conditioned place preference test, and intruder evoc aggression test, respectively. The obtained results showed that ethanol significantly increased locomotor activity, induced conditioned place preference in all animals, and, specifically, increased aggressivity in individually housed rats. These behavioural impairments induced by ethanol were associated with decreased glucocorticoid and mineralocorticoid receptors transcription in the prefrontal cortex. Notwithstanding, cannabidiol at a dose of 10 mg/kg significantly inhibited Et-OH-induced place preference in group-housed, but not in individually housed rats, and markedly inhibited the aggressive behaviour. These findings suggest that ethanol-induced behavioural impairments are dependent on the housing condition that may affect corticosterone receptors expression and subsequently the animal responsivity to cannabidiol treatment.


Subject(s)
Aggression/drug effects , Cannabidiol/pharmacology , Conditioning, Classical/drug effects , Ethanol/pharmacology , Animals , Behavior, Animal/drug effects , Housing, Animal , Locomotion/drug effects , Male , Prefrontal Cortex/metabolism , Rats , Rats, Wistar , Reward
4.
J Neurovirol ; 27(2): 325-333, 2021 04.
Article in English | MEDLINE | ID: mdl-33710598

ABSTRACT

The incidence of HIV-associated neurocognitive disorder (HAND) continues despite the introduction of combination antiretroviral drugs (cART). Several studies have reported the neurotoxicity of individual antiretroviral drugs (monotherapy), while the common approach for HIV treatment is through cART. Hence, the current study investigated the effects of long-term exposure to cART on cognitive function, oxidative damage, autophagy, and neuroplasticity in the hippocampus of mice. Female Balb/c mice received a once-a-day oral dose of cART composed of emtricitabine + tenofovir disoproxil fumarate or vehicle for 8 weeks. On week 7 of drug administration, all mice were assessed for spatial learning in the Morris water maze (MWM), and then on week 8, mice were sacrificed, and hippocampal tissue dissected from the brain. For biochemical analyses, we measured the concentration of 4-hydroxynonenal, and the expression of autophagic marker LC3B, synaptophysin, and brain-derived neurotrophic factor (BDNF) in the hippocampus. Our results showed that cART exposure increased escape latency in the MWM test. The cART-treated mice also showed increased 4-hydroxynonenal concentration and expression of LC3B. Furthermore, cART treatment decreased the expression of synaptophysin and BDNF. These findings further support the evidence that cART may be neurotoxic and therefore may play a role in the neuropathogenesis of HAND.


Subject(s)
Anti-HIV Agents/toxicity , Cognition Disorders/chemically induced , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/toxicity , Hippocampus/drug effects , Neuronal Plasticity/drug effects , Animals , Female , Maze Learning/drug effects , Mice , Mice, Inbred BALB C
5.
Life Sci ; 253: 117692, 2020 Jul 15.
Article in English | MEDLINE | ID: mdl-32376271

ABSTRACT

BACKGROUND: Depression is the most significant cause of suicide among neuropsychiatric illnesses. Major depression further affects the quality of life in an individual with epilepsy. The treatment of depression in an epileptic patient could be very challenging because of drug selection or the fact that some antiepileptic drugs are known to cause depression. It has been shown that in addition to the known involvement of the serotonergic pathway in depression, the glutamatergic system is also involved in the evolution of the disease, but this knowledge is limited. This study assessed if induction of epilepsy in rats will cause depressive-like behavior, alters the concentrations of metabotropic receptor 5 (mGluR5), glutamate transport protein (GLAST), glutamate synthase (GS) and brain derived neurotrophic factor (BDNF). MATERIALS AND METHOD: Epilepsy was induced in rats by injecting Pentylenetetrazole at 35 mg/kg every other day. At kindle, rats were subjected to sucrose preference test (SPT) and forced swim test (FST) and decapitated 4 h later. Hippocampal tissue was collected and the BDNF concentration was measured with ELISA; mGluR5 and GS protein expression was measured using western blot while amygdala tissue was used for GLAST expression with flow cytometry. RESULTS: Our results showed that epilepsy leads to depressive-like behavior in rats and alters the glutamatergic system. CONCLUSION: Therefore, we conclude that targeting the glutamate pathway may be a good strategy to alleviate depressive-like behavior associated with epilepsy.


Subject(s)
Depression/physiopathology , Epilepsy/physiopathology , Glutamic Acid/metabolism , Seizures, Febrile/physiopathology , Amygdala/metabolism , Animals , Brain-Derived Neurotrophic Factor/metabolism , Excitatory Amino Acid Transporter 1/metabolism , Glutamate Synthase/metabolism , Hippocampus/metabolism , Male , Pentylenetetrazole/administration & dosage , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5/metabolism
6.
Neurobiol Dis ; 136: 104701, 2020 03.
Article in English | MEDLINE | ID: mdl-31837421

ABSTRACT

HIV-associated neurocognitive impairments (HANI) are a spectrum of neurological disorders due to the effects of HIV-1 on the central nervous system (CNS). The HIV-1 subtypes; HIV-1 subtype B (HIV-1B) and HIV-1 subtype C (HIV-1C) are responsible for the highest prevalence of HANI and HIV infections respectively. The HIV transactivator of transcription (Tat) protein is a major contributor to the neuropathogenesis of HIV. The effects of the Tat protein on cells of the CNS is determined by the subtype-associated amino acid sequence variations. The extent to which the sequence variation between Tat-subtypes contribute to underlying mechanisms and neurological outcomes are not clear. In this review of the literature, we discuss how amino acid variations between HIV-1B Tat (TatB) and HIV-1C Tat (TatC) proteins contribute to the potential underlying neurobiological mechanisms of HANI. Tat-C is considered to be a more effective transactivator, whereas Tat-B may exert increased neurovirulence, including neuronal apoptosis, monocyte infiltration into the brain, (neuro)inflammation, oxidative stress and blood-brain barrier damage. These findings support the premise that Tat variants from different HIV-1 subtypes may direct neurovirulence and neurological outcomes in HANI.


Subject(s)
HIV Infections/genetics , HIV-1/genetics , Neurocognitive Disorders/genetics , tat Gene Products, Human Immunodeficiency Virus/genetics , Amino Acid Sequence , HIV Infections/epidemiology , HIV Infections/metabolism , HIV-1/metabolism , Humans , Inflammation Mediators/metabolism , Neurocognitive Disorders/epidemiology , Neurocognitive Disorders/metabolism , Transcription, Genetic/genetics , tat Gene Products, Human Immunodeficiency Virus/metabolism
7.
Brain Res Bull ; 155: 137-144, 2020 02.
Article in English | MEDLINE | ID: mdl-31837458

ABSTRACT

Epilepsy is a debilitating neurological illness that affects all aspect of an individual life. Despite advancement in research there is little reduction in the incidence of this disease. Prolonged febrile seizure (PFS) has been linked to epilepsy however, the pathophysiology of this is still not clear. We therefore looked at the effect of PFS on the development of epilepsy in a pentylenetetrazole (PTZ) rat model of epilepsy. A total of 42 male Sprague-Dawley rats were used for the experiment. On post-natal day (PND) 14, PFS was induced in 14 rats. This was followed by the induction of epilepsy in the 14 PFS animal and 14 animals from the remaining 28 rats by an initial injection of PTZ at a dose of 60 mg/kg on day one followed by 35 mg/kg on alternate day until kindle. We looked at the effect of PFS on the onset and the stage of convulsion at kindle. We also observed it effect on the hippocampal glial fibrillary acidic protein (GFAP), synaptophysin and metabotropic glutamate receptor 3 (mGluR3) expression measured with immunofluorescence, LI Cor Tissue florescence and immunohistochemistry respectively. Our study showed that PFS reduced seizure threshold by decreasing the time it took animals to kindle and also increased the stage of convulsion. The hippocampal GFAP, synaptophysin and mGluR3 expressions where upregulated in PTZ rats with PFS history when compared to PTZ rats alone.These findings indicated that PFS may increase the severity of epilepsy and alter brain expression of GFAP, synaptophysin and mGluR3 proteins.


Subject(s)
Epilepsy/physiopathology , Seizures, Febrile/physiopathology , Animals , Disease Models, Animal , Epilepsy/chemically induced , Glial Fibrillary Acidic Protein/drug effects , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Male , Pentylenetetrazole/administration & dosage , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Seizures, Febrile/chemically induced , Severity of Illness Index , Synaptophysin/metabolism
8.
J Chem Neuroanat ; 94: 86-92, 2018 12.
Article in English | MEDLINE | ID: mdl-30336207

ABSTRACT

The use of combination antiretroviral therapy (cART) has been successful in suppressing HIV-1 replication and restoring peripheral immune functioning in HIV-infected individuals. Despite these advances in the management of HIV, neurocognitive impairments continue to be diagnosed in HIV-infected patients on treatment, even when the viral load is low. Of interest is the observation that deficiencies in brain function in these individuals are marked by a persistent presence of neuroinflammation. Therefore, in this study we investigated whether long-term exposure to ART could contribute to neuroinflammation. Mice were subsequently administered a daily single dose of either Tenofovir disoproxil fumarate or Nevirapine orally for 8 weeks. After treatment, hippocampal tissue was collected from the brains of drug-treated and control mice and the levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and brain-derived neurotrophic factor (BDNF) determined. Our results showed that administration of Tenofovir disoproxil fumarate and Nevirapine induced astrogliosis and up-regulated IL-1ß and TNF-α. In addition, we found that Nevirapine reduced the expression of BDNF. Together these results suggest that Nevirapine promotes inflammatory and reduces neuroprotective processes in the hippocampus of mice. Our findings therefore highlight the potential of ART to be harmful to the brain and as such these drugs may contribute to the development of HIV-associated neurocognitive disorder (HAND).


Subject(s)
Anti-Retroviral Agents/administration & dosage , Encephalitis/chemically induced , Hippocampus/drug effects , Neuronal Plasticity/drug effects , Nevirapine/administration & dosage , Tenofovir/administration & dosage , Animals , Anti-Retroviral Agents/adverse effects , Brain-Derived Neurotrophic Factor/metabolism , Encephalitis/metabolism , Encephalitis/pathology , Hippocampus/metabolism , Hippocampus/pathology , Interleukin-1beta/metabolism , Mice , Nevirapine/adverse effects , Tenofovir/adverse effects , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL
...