Abstract:
Neuroinflammation is a hallmark of various neurodegenerative disorders, yet effective treatments remain limited. This study investigates the neuroprotective potential of a cannabidiol (CBD)-Rich Cannabis sativa L. (CS) extract in a lipopolysaccharide (LPS)-induced neuroinflammation mouse model. The effects on anxiety-like behavior, cognitive function, and locomotor activity were assessed using behavioral tests (open field, elevated plus maze, novel object recognition, and Morris water maze). Antioxidant activity was measured by assaying glutathione (GSH) levels and lipid peroxidation by-products (TBARs). Anti-inflammatory properties were evaluated using quantitative reverse transcription polymerase chain reaction (QRt-PCR) for proinflammatory cytokines (IL-6 and TNF-alpha), glial fibrillary acidic protein (GFAP), and cannabinoid receptor 1 (CB1) mRNAs in the prefrontal cortex (PFC). Astrocytic bioenergetics were analyzed using extracellular flux assays. Additionally, computational inference with a deep learning approach was conducted to evaluate the synergistic interactions among CS phytocompounds on the CB1 receptors. Compared with synthetic CBD, the CS extract (20.0 mg/kg) demonstrated superior efficacy in mitigating LPS-induced anxiety-like behavior, cognitive deficits, and locomotor impairments. It also significantly mitigated oxidative stress (increased GSH, reduced TBARs) and suppressed proinflammatory cytokines and GFAP mRNAs, indicating potent anti-inflammatory properties. The extract modulated CB1 receptor expression and preserved metabolic homeostasis in cortical astrocytes, preventing their shift from glycolysis to oxidative phosphorylation under neuroinflammatory conditions. Computational modeling highlighted conformational changes in CB1 receptor residues induced by Delta-9-THC that enhanced CBD binding. These findings underscore the potential of CS extract as a therapeutic candidate for managing neuroinflammation and its associated neurodegenerative consequences, warranting further clinical exploration.

Abstract:
The legalization of cannabis for industrial and medicinal purposes has significantly expanded worldwide. This study delves into the analgesic potential toxicity study of chloroformic extract from the Moroccan Cannabis sativa L. (C. sativa) cultivar, Khardala (KH extract). Our findings reveal that the lethal dose of KH extract is >/=5,000 mg/kg, with mice given 2,000 mg/kg exhibiting neurotoxic symptoms, including piloerection, aggressiveness, and fear, along with marked hepato-renal toxicity indicated by elevated levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, and creatinine in both male and female subjects. Importantly, no toxicity was observed at 250 mg/kg and 500 mg/kg doses. Remarkably, at a dose of 500 mg/kg, the KH extract demonstrated a potent analgesic effect superior to cannabidiol (CBD), suggesting a synergistic interaction among the extract's bioactive compounds, such as CBD, cannabidivarin (CBDV), Delta 9 tetrahydrocannabinol (THC), cannabigerol (CBG), Delta 9 tetrahydrocannabivarin (THCV), and beta-caryophyllene. In silico analysis supports these findings, showing the strong binding potential of THC, THCV, CBG, and CBDV to delta opioid receptors, with G-scores >-5.0 kcal/mol, highlighting the promising analgesic efficacy of this cannabis cultivar extract. This study underscores the therapeutic potential of the KH cultivar, positioning it as a promising candidate for pain management therapies.

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 Delta-FOSB expression in the nucleus accumbens (Nac), elevate CX3CL1 levels in both the ventral tegmental area and prefrontal cortex (PFC), and concurrently reduce IL-1beta 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.

Abstract:
INTRODUCTION: Aging is often linked to oxidative stress, where the body experiences increased damage from free radicals. Plants are rich sources of antioxidants, playing a role in slowing down aging and supporting the proper functioning and longevity of cells. Our study focuses on exploring the impact of Mentha rotundifolia (MR) and Salvia officinalis (SO) hydrosols on aging-related comorbidities. METHODS: The chemical composition of MR and SO hydrosols was analyzed by gas chromatography coupled to mass spectrometry. 2,2-Diphenyl 1-picrylhydrazyl and 2,20-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid radicals scavenging assays were used to assess their in vitro antioxidant activity, and heat induced albumin denaturation test was used to evaluate their anti-inflammatory activity. Subsequently, we administered 5% of each plant hydrosol in the drinking water of 18-month-old rats for six months. We then conducted behavioral tests, including open field, dark/light box, rotarod, and Y-maze assessments, and measured biochemical parameters in plasma, liver and brain tissues. RESULTS AND DISCUSSION: At two years old, animals treated with MR and SO hydrosols displayed fewer physical and behavioral impairments, along with well-preserved redox homeostasis in comparison with animals in the control group. These results highlighted the significance of MR and SO hydrosols in addressing various aspects of age-related comorbidities. The study suggests that these plant-derived hydrosols may have potential applications in promoting healthy aging and mitigating associated health challenges.

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 alpha (TNFalpha) 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.

Abstract:
Activation of the apoptotic pathway has been associated with promoting neuronal cell death in the pathophysiology of Parkinson disease (PD). Nonetheless, the mechanisms by which it may occur remain unclear. It has been suggested that stress-induced oxidation and potential apoptosis may play a major role in the progression of PD. Thus, in this study, we aimed to investigate the effect of subchronic restraint stress on striatal dopaminergic activity, iron, p53, caspase-3, and plasmatic acetylcholinesterase (AChE) levels in male Wistar rat model of PD induced by administration of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB). The obtained results showed that restraint stress exacerbates motor coordination deficits and anxiety in animals treated with 6-OHDA in comparison to animals receiving saline, and it had no effect on object recognition memory. On another hand, 6-OHDA decreased dopamine (DA) levels, increased iron accumulation, and induced overexpression of the pro-apoptotic factors caspase-3, p53, and AChE. More interestingly, post-lesion restraint stress exacerbated the expression of caspase-3 and AChE without affecting p53 expression. These findings suggest that subchronic stress may accentuate apoptosis and may contribute to DA neuronal loss in the striatal regions and possibly exacerbate the progression of PD.

Abstract:
BACKGROUND: Paraquat (1,1'-dimethyl-4-4'-bipyridinium dichloride) exposure is well-established as a neurotoxic agent capable of causing neurological deficits in offspring. This study aimed to investigate therapeutic effects of Arbutus unedo L. aqueous extract (AU) against paraquat (PQ) exposure. METHODS: For that the phytoconstituents of AU was determined by LC/MS, and then its antioxidant potential was assessed by DPPH and ABTS assays. The assessment included its impact on cell viability and mitochondrial metabolism using N27 dopaminergic cells. Additionally, we evaluated the effects of prenatal PQ exposure on motor coordination, dopamine levels, trace element levels, and total antioxidant capacity (TAC) in rat progeny. RESULTS: The phytochemical profile of AU extract revealed the presence of 35 compounds, primarily phenolic and organic acids, and flavonoids. This accounted for its strong in vitro antioxidant activities against DPPH and ABTS radicals, surpassing the activities of vitamin C. Our findings demonstrated that AU effectively inhibited PQ-induced loss of N27 rat dopaminergic neural cells and significantly enhanced their mitochondrial respiration. Furthermore, daily post-treatment with AU during the 21 days of the rat's pregnancy alleviated PQ-induced motor deficits and akinesia in rat progeny. These effects inhibited dopamine depletion and reduced iron levels in the striatal tissues. The observed outcomes appeared to be mediated by the robust antioxidant activity of AU, effectively counteracting the PQ-induced decrease in TAC in the blood plasma of rat progeny. These effects could be attributed to the bioactive compounds present in AU, including phenolic acids such as gallic acid and flavonoids such as quercetin, rutin, apigenin, glucuronide, and kaempferol, all known for their potent antioxidant capacity. DISCUSSION: In conclusion, this preclinical study provided the first evidence of the therapeutic potential of AU extract against PQ-induced neurotoxicity. These findings emphasize the need for further exploration of the clinical applicability of AU in mitigating neurotoxin-induced brain damage.