scholarly journals Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Felipe Patricio ◽  
Alan Axel Morales-Andrade ◽  
Aleidy Patricio-Martínez ◽  
Ilhuicamina Daniel Limón
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Subcortical Structures ◽  
6 Hydroxydopamine

The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson’s disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the nigro-striatal pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.

scholarly journals Therapeutic Potential of Repeated Intravenous Transplantation of Human Adipose-Derived Stem Cells in Subchronic MPTP-Induced Parkinson’s Disease Mouse Model

2020 ◽  
Vol 21 (21) ◽  
pp. 8129
Author(s):  
Hyunjun Park ◽  
Keun-A Chang
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Therapeutic Potential ◽  
Adipose Derived Stem Cells ◽  
Nigrostriatal Pathway

Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is clinically and pathologically characterized by motor dysfunction and the loss of dopaminergic neurons in the substantia nigra, respectively. PD treatment with stem cells has long been studied by researchers; however, no adequate treatment strategy has been established. The results of studies so far have suggested that stem cell transplantation can be an effective treatment for PD. However, PD is a progressively deteriorating neurodegenerative disease that requires long-term treatment, and this has been insufficiently studied. Thus, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASC) for repeated vein transplantation over long-term in an animal model of PD. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice, hASCs were administered on the tail vein six times at two-week intervals. After the last injection of hASCs, motor function significantly improved. The number of dopaminergic neurons present in the nigrostriatal pathway was recovered using hASC transplantation. Moreover, the administration of hASC restored altered dopamine transporter expression and increased neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), in the striatum. Overall, this study suggests that repeated intravenous transplantation of hASC may exert therapeutic effects on PD by restoring BDNF and GDNF expressions, protecting dopaminergic neurons, and maintaining the nigrostriatal pathway.

scholarly journals KDS2010, a Newly Developed Reversible MAO-B Inhibitor, as an Effective Therapeutic Candidate for Parkinson’s Disease

2021 ◽  
Author(s):  
Min-Ho Nam ◽  
Jong-Hyun Park ◽  
Hyo Jung Song ◽  
Ji Won Choi ◽  
Siwon Kim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Therapeutic Potential ◽  
Motor Dysfunction ◽  
Monoamine Oxidase B ◽  
Nigrostriatal Pathway ◽  
Neuroprotective Effects ◽  
Mao B ◽  
6 Hydroxydopamine ◽  
Mptp Model

AbstractMonoamine oxidase-B (MAO-B) is a well-established therapeutic target for Parkinson’s disease (PD); however, previous clinical studies on currently available irreversible MAO-B inhibitors have yielded disappointing neuroprotective effects. Here, we tested the therapeutic potential of KDS2010, a recently synthesized potent, selective, and reversible MAO-B inhibitor in multiple animal models of PD. We designed and synthesized a series of α-aminoamide derivatives and found that derivative KDS2010 exhibited the highest potency, specificity, reversibility, and bioavailability (> 100%). In addition, KDS2010 demonstrated significant neuroprotective and anti-neuroinflammatory efficacy against nigrostriatal pathway destruction in the mouse MPTP model of parkinsonism. Treatment with KDS2010 also alleviated parkinsonian motor dysfunction in 6-hydroxydopamine-induced and A53T mutant α-synuclein overexpression rat models of PD. Moreover, KDS2010 showed virtually no toxicity or side effects in non-human primates. KDS2010 could be a next-generation therapeutic candidate for PD.

Endocannabinoids and Food Intake: Newborn Suckling and Appetite Regulation in Adulthood

2005 ◽  
Vol 230 (4) ◽  
pp. 225-234 ◽  
Author(s):  
Ester Fride ◽  
Tatyana Bregman ◽  
Tim C. Kirkham
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Critical Role ◽  
Growth Failure ◽  
Endocannabinoid System ◽  
Failure To Thrive ◽  
Receptor Activation ◽  
Organ Systems

The appetite-stimulating effects of the cannabis plant (Cannabis sativa) have been known since ancient times, and appear to be effected through the incentive and rewarding properties of foods. Investigations into the biological basis of the multiple effects of cannabis have yielded important breakthroughs in recent years: the discovery of two cannabinoid receptors in brain and peripheral organ systems, and endogenous ligands (endocannabinoids) for these receptors. These advances have greatly increased our understanding of how appetite is regulated through these endocannabinoid receptor systems. The presence of endocannabinoids in the developing brain and in maternal milk have led to evidence for a critical role for CB, receptors in oral motor control of suckling during neonatal development. The endocannabinoids appear to regulate energy balance and food intake at four functional levels within the brain and periphery: (i) limbic system (for hedonic evaluation of foods), (ii) hypothalamus and hindbrain (integrative functions), (iii) intestinal system, and (iv) adipose tissue. At each of these levels, the endocannabinoid system interacts with a number of better known molecules involved in appetite and weight regulation, including leptin, ghrelin, and the melanocortins. Therapeutically, appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer, acquired immunodeficiency syndrome, or anorexia nervosa. The recent advances in cannabinoid pharmacology may lead to improved treatments for these conditions or, conversely, for combating excessive appetite and body weight, such as CB, receptor antagonists as antiobesity medications. In conclusion, the exciting progress in the understanding of how the endocannabinoid CB receptor systems influence appetite and body weight is stimulating the development of therapeutic orexigenic and anorectic agents. Furthermore, the role of cannabinoid CB, receptor activation for milk suckling in newborns may open new doors toward understanding nonorganic failure-to-thrive in infants, who display growth failure without known organic cause.

scholarly journals Gastric Helicobacter suis Infection Partially Protects against Neurotoxicity in A 6-OHDA Parkinson’s Disease Mouse Model

2021 ◽  
Vol 22 (21) ◽  
pp. 11328
Author(s):  
Helena Berlamont ◽  
Arnout Bruggeman ◽  
Eva Bauwens ◽  
Charysse Vandendriessche ◽  
Elien Clarebout ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Neuroprotective Effect ◽  
Cell Loss ◽  
Antioxidant Genes ◽  
Exact Etiology ◽  
Gastric Biopsies ◽  
6 Hydroxydopamine

The exact etiology of Parkinson’s disease (PD) remains largely unknown, but more and more research suggests the involvement of the gut microbiota. Interestingly, idiopathic PD patients were shown to have at least a 10 times higher prevalence of Helicobacter suis (H. suis) DNA in gastric biopsies compared to control patients. H. suis is a zoonotic Helicobacter species that naturally colonizes the stomach of pigs and non-human primates but can be transmitted to humans. Here, we investigated the influence of a gastric H. suis infection on PD disease progression through a 6-hydroxydopamine (6-OHDA) mouse model. Therefore, mice with either a short- or long-term H. suis infection were stereotactically injected with 6-OHDA in the left striatum and sampled one week later. Remarkably, a reduced loss of dopaminergic neurons was seen in the H. suis/6-OHDA groups compared to the control/6-OHDA groups. Correspondingly, motor function of the H. suis-infected 6-OHDA mice was superior to that in the non-infected 6-OHDA mice. Interestingly, we also observed higher expression levels of antioxidant genes in brain tissue from H. suis-infected 6-OHDA mice, as a potential explanation for the reduced 6-OHDA-induced cell loss. Our data support an unexpected neuroprotective effect of gastric H. suis on PD pathology, mediated through changes in oxidative stress.

scholarly journals Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions

2020 ◽  
Vol 21 (17) ◽  
pp. 6235
Author(s):  
Tapan Behl ◽  
Gagandeep Kaur ◽  
Simona Bungau ◽  
Rishabh Jhanji ◽  
Arun Kumar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cannabinoid Receptors ◽  
Life Quality ◽  
Endocannabinoid System ◽  
Therapeutic Interventions ◽  
Diseased State ◽  
Preclinical And Clinical Studies ◽  
Signalling Systems

Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state. Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD. These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression. Published papers to date were searched via MEDLINE, PubMed, etc., using specific key words in the topic of our manuscript. Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD. Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD). More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD.

scholarly journals Rhododendrin-Induced RNF146 Expression via Estrogen Receptor β Activation is Cytoprotective Against 6-OHDA-Induced Oxidative Stress

2019 ◽  
Vol 20 (7) ◽  
pp. 1772 ◽  
Author(s):  
Hyojung Kim ◽  
Jisoo Park ◽  
HyunHee Leem ◽  
MyoungLae Cho ◽  
Jin-Ha Yoon ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Estrogen Receptor ◽  
Nuclear Translocation ◽  
Ring Finger ◽  
Cell Loss ◽  
Receptor Activation ◽  
Estrogen Receptor Β ◽  
Dopaminergic Cell ◽  
6 Hydroxydopamine

Ring finger protein 146 (RNF146) is an E3 ubiquitin ligase whose activity prevents poly (ADP-ribose) polymerase 1 (PARP1)-dependent neurodegeneration in Parkinson’s disease (PD). Previously, we reported that rhododendrin is a chemical inducer that increases RNF146 expression. However, the molecular mechanism of rhododendrin-induced RNF146 expression is largely unknown and its translational application for the treatment of Parkinson’s disease remains unexplored. Here we found that rhododendrin increased RNF146 expression via estrogen receptor β (ERβ) activation. Rhododendrin stimulated ERβ nuclear translocation and binding to the RNF146 promoter, thereby enhancing its transcription. Rhododendrin is cytoprotective against 6-hydroxydopamine (6-OHDA)-induced cell death, which is largely dependent on ERβ activity and RNF146 expression. Finally, we demonstrated that rhododendrin treatment resulted in RNF146 expression in dopaminergic neurons in mice. Moreover, dopaminergic neuron viability was markedly enhanced by pretreatment with rhododendrin in 6-OHDA-induced mouse models for PD. Our findings indicate that estrogen receptor activation plays a neuroprotective role and that rhododendrin could be a potential therapeutic agent in preventing PARP1-dependent dopaminergic cell loss in PD.

scholarly journals Antioxidative and Anti-Inflammatory Properties of Cannabidiol

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 21 ◽  
Author(s):  
Sinemyiz Atalay ◽  
Iwona Jarocka-Karpowicz ◽  
Elzbieta Skrzydlewska
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Biological Effects ◽  
Antioxidant Properties ◽  
Endocannabinoid System ◽  
Anti Inflammatory ◽  
Pharmacologically Active ◽  
Preclinical And Clinical Studies ◽  
Synthetic Derivatives

Cannabidiol (CBD) is one of the main pharmacologically active phytocannabinoids of Cannabis sativa L. CBD is non-psychoactive but exerts a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties. The chemistry and pharmacology of CBD, as well as various molecular targets, including cannabinoid receptors and other components of the endocannabinoid system with which it interacts, have been extensively studied. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential of CBD for many diseases, including diseases associated with oxidative stress. Here, we review the main biological effects of CBD, and its synthetic derivatives, focusing on the cellular, antioxidant, and anti-inflammatory properties of CBD.

scholarly journals Enhanced Neuroprotective Effects of Coadministration of Tetrandrine with Glutathione in Preclinical Model of Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Xiang-Yun Li ◽  
Guang-Hai Mei ◽  
Qiang Dong ◽  
Yu Zhang ◽  
Zhuang-Li Guo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Survival ◽  
Neuroprotective Effect ◽  
Redox System ◽  
Rotational Behavior ◽  
Preclinical Model ◽  
Neuroprotective Effects ◽  
6 Hydroxydopamine

Aim. In this study we examined the influence of tetrandrine (Tet) on the neuroprotective effects of glutathione (GSH) in the 6-hydroxydopamine- (6-OHDA-) lesioned rat model of Parkinson’s disease (PD).Methods. Levels in the redox system, dopamine (DA) metabolism, dopaminergic neuronal survival, and apoptosis of the substantia nigra (SN) and striatum, as well as the rotational behavior of animals were examined after a 50-day administration of GSH + Tet (or GSH) and/or L-3,4-dihydroxyphenylalanine (L-dopa) to PD rats. Ethics Committee of Huashan Hospital, Fudan University approved the protocol (number SYXK2009-0082).Results. Administration of GSH or Tet alone did not show any significant effects on the factors evaluated in the PD rats. However, in the GSH + Tet group, we observed markedly decreased oxidative damage, inhibition of DA metabolism and enhanced DA synthesis, increased tyrosine hydroxylase- (TH-) immunopositive neuronal survival, and delayed apoptosis of dopaminergic neurons in the SN. Animal rotational behavior was improved in the GSH + Tet group. Additionally, coadministration of GSH + Tet appeared to offset the possible oxidative neurotoxicity induced by L-dopa.Conclusion. In this study, we demonstrated that tetrandrine allowed occurrence of the neuroprotective effect of glutathione probably due to inhibition of P-glycoprotein on 6-hydroxydopamine-lesioned rat models of Parkinson’s disease, including rats undergoing long-term L-dopa treatment.

P.773 Therapeutic potential of bromelain in 6-hydroxydopamine rat model of parkinson's disease

2020 ◽  
Vol 40 ◽  
pp. S438-S439
Author(s):  
B. Çiçek ◽  
M. Gul ◽  
A. Taghizadehghalehjoughi ◽  
U. Okkay ◽  
S. Yildirim ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Therapeutic Potential ◽  
6 Hydroxydopamine
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