High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson's disease patients

Pisani, Antonio; Fezza, Filomena; Galati, Salvatore; Battista, Natalia; Napolitano, Simone; Finazzi‐Agrò, Alessandro; Bernardi, Giorgio; Brusa, Livia; Pierantozzi, Mariangela; Stanzione, Paolo; Maccarrone, Mauro

doi:10.1002/ana.20462

Cited by 195 publications

(101 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1) assayed in probes drawn from Parkinson patients and healthy controls. The assessment of lipid markers in the context of Parkinson's disease is based on evidence of an involvement of lipid regulation [15][16][17][18][19][20][21].…”

Section: Biomedical Data Setmentioning

confidence: 99%

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

et al. 2018

View full text Add to dashboard Cite

Background: Unsupervised machine-learned analysis of cluster structures, applied using the emergent self-organizing feature maps (ESOM) combined with the unified distance matrix (U-matrix) has been shown to provide an unbiased method to identify true clusters. It outperforms classical hierarchical clustering algorithms that carry a considerable tendency to produce erroneous results. To facilitate the application of the ESOM/U-matrix method in biomedical research, we introduce the interactive R-based bioinformatics tool "Umatrix", which enables valid identification of a biologically meaningful cluster structure in the data by training a Kohonen-type self-organizing map followed by interface-guided interactive clustering on the emergent U-matrix map. Results: The ability to detect clinical relevant subgroups was applied to a data set comprising plasma concentrations of d = 25 lipid markers including endocannabinoids, lysophosphatidic acids, ceramides and sphingolipids acquired from n = 100 patients with Parkinson's disease and n = 100 controls. Following ESOM training, clear data structures in the high-dimensional data space were observed on the U-matrix, allowing separation of patients from controls almost perfectly. When the data structure was destroyed by Monte-Carlo random resampling, the U-matrix became unstructured and patients and controls were mixed. Obtained results are biologically plausible and supported by empirical evidence of a regulation of several classes of lipids in Parkinson's disease. Conclusions: Sophisticated analysis of structures in biomedical data provides a basis for the mechanistic interpretation of the observations and facilitates subsequent analyses focusing on hypothesis testing. The freely available R library "Umatrix" provides an interactive tool for broader application of unsupervised machine learning on complex biomedical data.

show abstract

Section: Biomedical Data Setmentioning

confidence: 99%

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Again, these pharmacological effects may be influenced by the changes that the endocannabinoid system experienced in this disease, as revealed by the data collected in postmortem tissues and biological fluids [114,118,119], as well as those found in animal models [111,113,118,120]. They include: 1) the upregulation of CB 1 R in striatal neurons under the control of dopaminergic neurons that degenerate in PD, as observed in postmortem tissue from patients and in different experimental models of the disease (reviewed in [108]); 1) the elevation of CB 2 R in glia recruited to the lesion sites in the postmortem substantia nigra of patients with PD and in mice lesioned with MPTP or LPS [111,113,114]; and 3) the loss of neuronal CB 2 R in postmortem tissues of patients with PD due to the degeneration of nigrostriatal dopaminergic neurons [121,122].…”

Section: Cannabinoids and Chronic Neurodegenerative Disorders: II Pdmentioning

confidence: 99%

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

2015

View full text Add to dashboard Cite

Cannabinoids form a singular family of plantderived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

show abstract

“…Notably, AEA is increased in the cerebrospinal fluid of PD patients (34) and animal models of PD produced by administration of 6-OHDA (35). In an MPTP-treated macaque model, increases in AEA and 2-arachidonoylglycerol compensate for dopamine depletion (36).…”

Section: P Arkinson's Disease (Pd) Is a Common Neurodegenerativementioning

confidence: 99%

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Chung

Bok

Huh

et al. 2011

The Journal of Immunology

106

View full text Add to dashboard Cite

This study examined whether the cannabinoid receptor type 1 (CB1) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB1 receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB1 receptor. The present in vivo and in vitro findings clearly indicate that the CB1 receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson’s disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage.

show abstract

High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson's disease patients

Cited by 195 publications

References 5 publications

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Contact Info

Product

Resources

About