Possible actions of cannabidiol in obsessive-compulsive disorder by targeting the WNT/ß-catenin pathway.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and glutamatergic pathways play key roles in the causes of OCD. However, first-line therapies include cognitive-behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for new treatment is mandatory. This review focuses on the potential effects of cannabidiol (CBD), as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which CBD provides its benefit properties. CBD medication downregulates GSK-3ß, the main inhibitor of the WNT/ß-catenin pathway. The activation of the WNT/ß-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway and circadian rhythms dysregulation in OCD. Future prospective clinical trials could focus on CBD and its different and multiple interactions in OCD.

WNT/ß-catenin Pathway: a Possible Link Between Hypertension and Alzheimer's Disease.

PURPOSE OF REVIEW: Recent research has shown that older people with high blood pressure (BP), or hypertension, are more likely to have biomarkers of Alzheimer's disease (AD). Essential hypertension represents the most common cardiovascular disease worldwide and is thought to be responsible for about 13% of all deaths. People with essential hypertension who regularly take prescribed BP medications are half as likely to develop AD as those who do not take them. What then is the connection? RECENT FINDINGS: We know that high BP can damage small blood vessels in the brain, affecting those parts that are responsible for memory and thinking. However, the link between AD and hypertension remains unclear. Recent advances in the field of molecular and cellular biology have revealed a downregulation of the canonical WNT/ß-catenin pathway in both hypertension and AD. In AD, the glutamate transport function is decreased, a decrease that is associated with a loss of synapse and neuronal death. ß-catenin signaling appears to act as a major regulator of glutamate transporters (EAAT and GS) expression and can be harnessed to remove excess glutamate in AD. This review focuses on the possible link between hypertension and AD through the decreased WNT/ß-catenin which interacts with the glutamatergic pathway.

Cannabidiol and the Canonical WNT/ß-Catenin Pathway in Glaucoma.

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/ß-catenin pathway in glaucoma, associated with overactivation of the GSK-3ß signaling. WNT/ß-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/ß-catenin pathway and decrease of the GSK-3ß activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/ß-catenin pathway. CBD downregulates GSK3-ß activity, an inhibitor of WNT/ß-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/ß-catenin pathway.

PPARγ agonists: potential treatment for autism spectrum disorder by inhibiting the canonical WNT/ß-catenin pathway.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a deficit in social interactions and communication with repetitive and restrictive behavior. No curative treatments are available for ASD. Pharmacological treatments do not address the core ASD behaviors, but target comorbid symptoms. Dysregulation of the core neurodevelopmental pathways is associated with the clinical presentation of ASD, and the canonical WNT/ß-catenin pathway is one of the major pathways involved. The canonical WNT/ß-catenin pathway participates in the development of the central nervous system, and its dysregulation involves developmental cognitive disorders. In numerous tissues, the canonical WNT/ß-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) act in an opposed manner. In ASD, the canonical WNT/ß-catenin pathway is increased while PPARγ seems to be decreased. PPARγ agonists present a beneficial effect in treatment for ASD children through their anti-inflammatory role. Moreover, they induce the inhibition of the canonical WNT/ß-catenin pathway in several pathophysiological states. We focus this review on the hypothesis of an opposed interplay between PPARγ and the canonical WNT/ß-catenin pathway in ASD and the potential role of PPARγ agonists as treatment for ASD.

Circadian Rhythms in Exudative Age-Related Macular Degeneration: The Key Role of the Canonical WNT/ß-Catenin Pathway.

Age-related macular degeneration (AMD) is considered as the main worldwide cause of blindness in elderly adults. Exudative AMD type represents 10 to 15% of macular degeneration cases, but is the main cause of vision loss and blindness. Circadian rhythm changes are associated with aging and could further accelerate it. However, the link between circadian rhythms and exudative AMD is not fully understood. Some evidence suggests that dysregulation of circadian functions could be manifestations of diseases or could be risk factors for the development of disease in elderly adults. Biological rhythms are complex systems interacting with the environment and control several physiological pathways. Recent findings have shown that the dysregulation of circadian rhythms is correlated with exudative AMD. One of the main pathways involved in exudative AMD is the canonical WNT/ß-catenin pathway. Circadian clocks have a main role in some tissues by driving the circadian expression of genes involved in physiological and metabolic functions. In exudative AMD, the increase of the canonical WNT/ß-catenin pathway is enhanced by the dysregulation of circadian rhythms. Exudative AMD progression is associated with major metabolic reprogramming, initiated by aberrant WNT/ß-catenin pathway, of aerobic glycolysis. This review focuses on the interest of circadian rhythm dysregulation in exudative AMD through the aberrant upregulation of the canonical WNT/ß-catenin pathway.

Metabolic reprogramming in atherosclerosis: Opposed interplay between the canonical WNT/ß-catenin pathway and PPARγ.

Atherosclerosis, a chronic inflammatory and age-related disease, is a complex mechanism presenting a dysregulation of vessel structures. During this process, the canonical WNT/ß-catenin pathway is increased whereas PPARγ is downregulated. The two systems act in an opposite manner. This paper reviews the opposing interplay of these systems and their metabolic-reprogramming pathway in atherosclerosis. Activation of the WNT/ß-catenin pathway enhances the transcription of targets involved in inflammation, endothelial dysfunction, the proliferation of vascular smooth muscle cells, and vascular calcification. This complex mechanism, which is partly controlled by the WNT/ß-catenin pathway, presents several metabolic dysfunctions. This phenomenon, called aerobic glycolysis (or the Warburg effect), consists of a shift in ATP production from mitochondrial oxidative phosphorylation to aerobic glycolysis, leading to the overproduction of intracellular lactate. This mechanism is partially due to the injury of mitochondrial respiration and an increase in the glycolytic pathway. In contrast, PPARγ agonists downregulate the WNT/ß-catenin pathway. Therefore, the development of therapeutic targets, such as PPARγ agonists, for the treatment of atherosclerosis could be an interesting and innovative way of counteracting the canonical WNT pathway.

Hypothesis of Opposite Interplay Between the Canonical WNT/beta-catenin Pathway and PPAR Gamma in Primary Central Nervous System Lymphomas.

Primary central nervous system lymphomas (PCNSLs) are angiocentric neoplasia which present dense monoclonal lymphocyte proliferation, and occur in brain parenchyma in 90% of the cases. Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL) subtype represents more than 90% of PCNSLs and is the most aggressive subtype with a cure rate of only 40%. One of the characteristics of ABC-DLBCL subtype is neuroinflammation through the activation of NF-kappaB pathway. c-Myc alterations and protein expression have been shown in aggressive DLBCL. c-Myc is considered as a key prognostic and predictive biomarker for survival in DLBCL, its expression is associated with worst survival rates. Although mRNA of c-Myc is increased by low levels gains of c-Myc, several studies have shown that c-Myc protein expression is overexpressed without c-Myc abnormalities. These high levels of c-Myc protein in DLBCL without genetic abnormalities suggest that c-Myc protein expression may be also increased by other mechanisms or signaling pathways which regulate its expression. In PCNSLs, the canonical WNT/beta- catenin pathway is upregulated while PPAR gamma is downregulated. The opposite interplay between WNT/beta-catenin pathway and PPAR gamma is reviewed here. Activation of WNT/beta-catenin pathway leads to the transcription of genes involved in cell proliferation, mitochondrial metabolism, protein synthesis, and tumor growth, such as c-Myc. PPAR gamma agonists induce the inhibition of several signaling pathways such as NF-kappaB, STAT, PI3K/Akt and WNT/beta-catenin pathway. Activation of PPAR gamma agonists may have a major negative key role in the regulation of PCNSLs progression.

Circadian Rhythms and Energy Metabolism Reprogramming in Parkinson's Disease.

Entropy rate is increased by several metabolic and thermodynamic abnormalities in neurodegenerative diseases (NDs). Changes in Gibbs energy, heat production, ionic conductance or intracellular acidity are irreversible processes impelling modifications of the entropy rate. The present review focuses on the thermodynamic implications in the reprogramming of cellular energy metabolism enabling in Parkinson's disease (PD) through the contrasting interplay of the molecular signaling pathways WNT/ ß-catenin and PPARγ. In PD, WNT/ß-catenin pathway is downregulated while PPARγ is upregulated. Thermodynamic behaviors of metabolic enzymes are modified by dysregulation of the canonical WNT/ß-catenin pathway. Downregulation of WNT/ß-catenin pathway leads to hypometabolism, oxidative stress and cell death through inactivation of glycolytic enzymes such as Glut, PKM2, PDK1, MCT-1, LDH-A but also to activation of PDH. In addition, in NDs, PPARγ is dysregulated even though it contributes to the regulation of several key circadian genes. PD processes may be considered as dissipative structures that exchange energy or matter with their environment far-from the thermodynamic equilibrium. Far-from-equilibrium thermodynamics are notions driven by circadian rhythms, which directly contribute to regulation of the molecular pathways WNT/ß-catenin and PPARγ involved in the reprogramming of cellular energy metabolism enabling in Parkinson's disease.

Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis.

Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches.

Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/ß-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/ß-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4⁺ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/ß-catenin pathway. Upregulation of WNT/ß-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/ß-catenin signaling and demyelinating processes by inducing dysfunction of CD4⁺ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4⁺ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/ß-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

Effects of cannabidiol interactions with Wnt/ß-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease, in which the primary etiology remains unknown. AD presents amyloid beta (Aß) protein aggregation and neurofibrillary plaque deposits. AD shows oxidative stress and chronic inflammation. In AD, canonical Wingless-Int (Wnt)/ß-catenin pathway is downregulated, whereas peroxisome proliferator-activated receptor γ (PPARγ) is increased. Downregulation of Wnt/ß-catenin, through activation of glycogen synthase kinase-3ß (GSK-3ß) by Aß, and inactivation of phosphatidylinositol 3-kinase/Akt signaling involve oxidative stress in AD. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid from Cannabis sativa plant. In PC12 cells, Aß-induced tau protein hyperphosphorylation is inhibited by CBD. This inhibition is associated with a downregulation of p-GSK-3ß, an inhibitor of Wnt pathway. CBD may also increase Wnt/ß-catenin by stimulation of PPARγ, inhibition of Aß and ubiquitination of amyloid precursor protein. CBD attenuates oxidative stress and diminishes mitochondrial dysfunction and reactive oxygen species generation. CBD suppresses, through activation of PPARγ, pro-inflammatory signaling and may be a potential new candidate for AD therapy.

Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process.

Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor ß (TGF-ß) signaling and the canonical WNT/ß-catenin pathway, leading to aerobic glycolysis, called the Warburg effect. Molecular signaling pathways leading to fibrosis are considered dissipative structures that exchange energy or matter with their environment far from the thermodynamic equilibrium. The myofibroblastic cells arise from exergonic processes by switching the core metabolism from oxidative phosphorylation to glycolysis, which generates energy and reprograms cellular energy metabolism to induce the process of myofibroblast differentiation. Circadian rhythms are far-from-equilibrium thermodynamic processes. They directly participate in regulating the TGF-ß and WNT/ß-catenin pathways involved in energetic dysregulation and enabling fibrosis. The present review focusses on the thermodynamic implications of the reprogramming of cellular energy metabolism, leading to fibroblast differentiation into myofibroblasts through the positive interplay between TGF-ß and WNT/ß-catenin pathways underlying in fibrosis.

Predictive biomarkers of intra-ocular pressure decrease after cataract surgery associated with trabecular washout in patients with pseudo exfoliative glaucoma.

To investigate biomarkers of intra-ocular pressure (IOP) decrease after cataract surgery with trabecular washout in pseudo-exfoliative (PEX) glaucoma. A single-center observational prospective study in PEX glaucoma patients undergoing cataract surgery with trabecular washout (Goniowash) was performed from 2018 to 2021. Age, gender, visual acuity, IOP, endothelial cell count, central corneal thickness, medications, were collected over 16-month follow-up. Multivariable binomial regression models were implemented. 54 eyes (35 subjects) were included. Mean preoperative IOP (IOPBL) was 15.9 ± 3.5 mmHg. Postoperative IOP reduction was significant at 1-month and throughout follow-up (p < 0.01, respectively). IOPBL was a predictive biomarker inversely correlated to IOP decrease throughout follow-up (p < 0.001). At 1 and 12 months of follow-up, IOP decrease concerned 31 (57.4%) and 34 (63.0%) eyes with an average IOP decrease of 17.5% (from 17.6 ± 3.1 to 14.3 ± 2.2 mmHg) and 23.0% (from 17.7 ± 2.8 to 13.5 ± 2.6 mmHg), respectively. Performance (AUC) of IOPBL was 0.85 and 0.94 (p < 0.0001, respectively), with IOPBL threshold ≥ 15 mmHg for 82.1% and 96.8% sensitivity, 84.2% and 75.0% specificity, 1.84 and 3.91 IOP decrease odds-ratio, respectively. All PEX glaucoma patients with IOPBL greater than or equal to the average general population IOP were likely to achieve a significant sustainable postoperative IOP decrease.

On a minimal model for hemodynamics and metabolism of lactate: application to low grade glioma and therapeutic strategies.

WHO II low grade glioma evolves inevitably to anaplastic transformation. Magnetic resonance imaging is a good non-invasive way to watch it, by hemodynamic and metabolic modifications, thanks to multinuclear spectroscopy (1)H/(31)P. In this work we study a multi-scale minimal model of hemodynamics and metabolism applied to the study of gliomas. This mathematical analysis leads us to a fast-slow system. The control of the position of the stationary point brings to the concept of domain of viability. Starting from this system, the equations bring to light the parameters that push glioma cells out of their domain of viability. Four fundamental factors are highlighted. The first two are cerebral blood flow and the rate of lactate transport through monocarboxylate transporters, which must be reduced in order to push glioma out of its domain of viability. Another factor is the intra arterial lactate, which must be increased. The last factor is pH, indeed a decrease of intra cellular pH could interfere with glioma growth. These reflections suggest that these four parameters could lead to new therapeutic strategies for the management of low grade gliomas.

Machine learning decision tree models for multiclass classification of common malignant brain tumors using perfusion and spectroscopy MRI data.

Background: To investigate the contribution of machine learning decision tree models applied to perfusion and spectroscopy MRI for multiclass classification of lymphomas, glioblastomas, and metastases, and then to bring out the underlying key pathophysiological processes involved in the hierarchization of the decision-making algorithms of the models. Methods: From 2013 to 2020, 180 consecutive patients with histopathologically proved lymphomas (n = 77), glioblastomas (n = 45), and metastases (n = 58) were included in machine learning analysis after undergoing MRI. The perfusion parameters (rCBVmax, PSRmax) and spectroscopic concentration ratios (lac/Cr, Cho/NAA, Cho/Cr, and lip/Cr) were applied to construct Classification and Regression Tree (CART) models for multiclass classification of these brain tumors. A 5-fold random cross validation was performed on the dataset. Results: The decision tree model thus constructed successfully classified all 3 tumor types with a performance (AUC) of 0.98 for PCNSLs, 0.98 for GBM and 1.00 for METs. The model accuracy was 0.96 with a RSquare of 0.887. Five rules of classifier combinations were extracted with a predicted probability from 0.907 to 0.989 for that end nodes of the decision tree for tumor multiclass classification. In hierarchical order of importance, the root node (Cho/NAA) in the decision tree algorithm was primarily based on the proliferative, infiltrative, and neuronal destructive characteristics of the tumor, the internal node (PSRmax), on tumor tissue capillary permeability characteristics, and the end node (Lac/Cr or Cho/Cr), on tumor energy glycolytic (Warburg effect), or on membrane lipid tumor metabolism. Conclusion: Our study shows potential implementation of machine learning decision tree model algorithms based on a hierarchical, convenient, and personalized use of perfusion and spectroscopy MRI data for multiclass classification of these brain tumors.

Proton MR spectroscopy in predicting the increase of perfusion MR imaging for WHO grade II gliomas.

PURPOSE: To investigate the correlation between the metabolite ratios obtained from proton magnetic resonance (MR) spectroscopy and those obtained from MR perfusion parameters (relative cerebral blood volume [rCBV]) in a cohort of low-grade glioma (LGG). MATERIALS AND METHODS: Patients underwent prospectively conventional MR, proton magnetic resonance spectroscopy ((1) HMRS), and perfusion-weighted images (PWI). Statistical analyses were performed to determine the correlative and independent predictive factors of rCBVmax and the metabolite ratio thresholds with optimum sensitivity and specificity. RESULTS: Thirty-one patients were included in this study. Linear correlations were observed between the metabolic ratios (lactate [Lac]/creatine [Cr], choline [Cho]/N-acetyl-aspartate [NAA], free-lipids/Cr) and rCBVmax (P < 0.05). These metabolic ratios were determined to be independent predictive factors of rCBVmax (P = 0.027, 0.011 and 0.032, respectively). According to the receiver operating characteristic curves, the cutoff values of the metabolic ratios to discriminate between the two populations of rCBVmax (<1.7 versus = 1.7) were 1.72, 1.54, and 1.40, respectively, with a sensitivity = 75% and a specificity >95% for Lac/Cr. CONCLUSION: This study demonstrated consistent correlations between the data from (1) HMRS and PWI. The Lac/Cr ratio predicts regional hemodynamic changes, which are themselves a useful biomarker of clinical prognosis in patients with LGG. As such, this ratio may provide a new parameter for making improved clinical decisions.

WNT/ß-catenin pathway and circadian rhythms in obsessive-compulsive disorder.

The neuropsychiatric disease named obsessive-compulsive disorder is composed by obsessions and/or compulsions. Obsessive-compulsive disorder etiologies are undefined. However, numerous mechanisms in several localizations are implicated. Some studies showed that both glutamate, inflammatory factors and oxidative stress could have main functions in obsessive-compulsive disorder. Glycogen synthase kinase-3ß, the major negative controller of the WNT/ß-catenin pathway is upregulated in obsessive-compulsive disorder. In obsessive-compulsive disorder, some studies presented the actions of the different circadian clock genes. WNT/ß-catenin pathway and circadian clock genes appear to be intricate. Thus, this review focuses on the interaction between circadian clock genes and the WNT/ß-catenin pathway in obsessive-compulsive disorder.

Theoretical discrimination index of postural instability in amyotrophic lateral sclerosis.

To assess the usefulness of a theoretical postural instability discrimination index (PIth) in amyotrophic lateral sclerosis (ALS). Prospective regression analyzes were performed to identify the biomechanical determinants of postural instability unrelated to lower limb motor deficits from gait initiation factors. PIth was constructed using a logit function of biomechanical determinants. Discriminatory performance and performance differences were tested. Backward displacement of the pression center (APAamplitude) and active vertical braking of the mass center (Braking-index) were the biomechanical determinants of postural instability. PIth = - 0.13 × APAamplitude - 0.12 × Braking-index + 5.67, (P < 0.0001, RSquare = 0.6119). OR (APAamplitude) and OR (Braking-index) were 0.878 and 0.887, respectively, i.e., for a decrease of 10 mm in APAamplitude or 10% in Braking-index, the postural instability risk was 11.391 or 11.274 times higher, respectively. PIth had the highest discriminatory performance (AUC 0.953) with a decision threshold value [Formula: see text] 0.587, a sensitivity of 90.91%, and a specificity of 83.87%, significantly increasing the sensitivity by 11.11%. PIth, as objective clinical integrator of gait initiation biomechanical processes significantly involved in dynamic postural control, was a reliable and performing discrimination index of postural instability with a significant increased sensitivity, and may be useful for a personalized approach to postural instability in ALS.

Parkinson's Disease: Potential Actions of Lithium by Targeting the WNT/ß-Catenin Pathway, Oxidative Stress, Inflammation and Glutamatergic Pathway.

Parkinson's disease (PD) is one of the major neurodegenerative diseases (ND) which presents a progressive neurodegeneration characterized by loss of dopamine in the substantia nigra pars compacta. It is well known that oxidative stress, inflammation and glutamatergic pathway play key roles in the development of PD. However, therapies remain uncertain and research for new treatment is mandatory. This review focuses on the potential effects of lithium, as a potential therapeutic strategy, on PD and some of the presumed mechanisms by which lithium provides its benefit properties. Lithium medication downregulates GSK-3beta, the main inhibitor of the WNT/ß-catenin pathway. The stimulation of the WNT/ß-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway. Future prospective clinical trials could focus on lithium and its different and multiple interactions in PD.

Lithium: a potential therapeutic strategy in obsessive-compulsive disorder by targeting the canonical WNT/ß pathway.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized b-y recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and the glutamatergic pathway play key roles in the causes of OCD. However, first-line therapies include cognitive-behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for a new treatment is mandatory. This review focuses on the potential effects of lithium, as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which lithium provides its benefit properties. Lithium medication downregulates GSK-3ß, the main inhibitor of the WNT/ß-catenin pathway. The activation of the WNT/ß-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway. Future prospective clinical trials could focus on lithium and its different and multiple interactions in OCD.