Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE‐1 Inhibitors Against Alzheimer's Disease by In Silico, In Vitro, and In Vivo Studies

Article

Author: Masullo, Mariorosario ; Boccella, Serena ; Fusco, Antimo ; Nasso, Rosarita ; D'Errico, Antonio ; Karsak, Meliha ; Iannotti, Fabio Arturo ; Guida, Francesca ; Luongo, Livio ; Ricciardi, Federica ; Vitale, Rosa Maria ; Maione, Sabatino ; Morace, Andrea Maria ; Rading, Sebastian ; Arcone, Rosaria ; Amodeo, Pietro ; Caprioglio, Diego

ABSTRACTCannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget‐directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β‐amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β‐arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl‐ and butyryl‐cholinesterases (AChE/BuChE), as well as on β‐secretase‐1 (BACE‐1) enzymes in a low micromolar range, and they also prevent aggregation of β‐amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β‐amyloid peptide. A recovery of the long‐term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β‐arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti‐AD MTDLs.

International Journal of Molecular SciencesQ2 · BIOLOGY

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Q2 · BIOLOGY

ReviewOA

Author: Low, Zun Siong ; Tan, Wei Ren ; Lee, Justin Yin Hao ; Tan, Nguan Soon ; Cheng, Hong Sheng ; Marvalim, Charlie

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

Biomolecules

PPARα Signaling: A Candidate Target in Psychiatric Disorder Management

Review

Author: Braccagni, Giulia ; Pinna, Graziano ; De Montis, Maria Graziella ; Gambarana, Carla ; Scheggi, Simona

Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD.

100 Deals associated with PPARα/γ agonists(University of Bari)

R&D Status

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

PPARα/γ agonists(University of Bari)

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation