Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Journal of Biomedical Science, Journal Year: 2021, Volume and Issue: 28(1)

Published: Oct. 11, 2021

Abstract In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite tremendous effort devoted to understanding recent decades, treatment delay disease progression is largely ineffective and urgent demand. The development of new strategies targeting these pathological features a timely topic. It important note that most degenerative are associated accumulation specific misfolded proteins, which facilitated by several common (including poor energy homeostasis mitochondrial dysfunction). Adenosine purine nucleoside neuromodulator brain. also essential component production pathways, cellular metabolism, gene regulation brain cells. levels intracellular extracellular adenosine thus tightly controlled handful proteins metabolic enzymes transporters) maintain proper homeostasis. Notably, disruption under various pathophysiological conditions has been documented. past two receptors (particularly A 1 2A receptors) actively investigated as drug targets major diseases. Unfortunately, except for antagonist (istradefylline) administered adjuvant levodopa Parkinson’s disease, no effective based on developed this review, we summarize emerging findings involved control discuss challenges future prospects therapeutic treatments their disorders

Language: Английский

---

Cannabidiol Inhibition of Murine Primary Nociceptors: Tight Binding to Slow Inactivated States of Na_v1.8 Channels

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(30), P. 6371 - 6387

Published: June 15, 2021

The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to have analgesic effects in animal studies but little is known about its mechanism of action. We examined the CBD on intrinsic excitability primary pain-sensing neurons. Studying acutely dissociated capsaicin-sensitive mouse DRG neurons at 37°C, we found that effectively inhibited repetitive action potential firing, from 15–20 potentials evoked by 1 s current injections control 1–3 with 2 μm CBD. Reduction firing was accompanied a reduction height, widening potentials, afterhyperpolarization, and increased propensity enter depolarization block. Voltage-clamp experiments showed both TTX-sensitive TTX-resistant (TTX-R) sodium currents use-dependent manner. strong state-dependent inhibition TTX-R channels, fast binding inactivated channels during depolarizations slow unbinding repolarization. alteration channel availability various voltages suggested binds especially tightly [K_d (dissociation constant), ∼150 nm] state which can be substantially occupied as negative −40 mV. Remarkably, more potent inhibiting than local anesthetic bupivacaine. conclude might produce some direct neuronal excitability, tight Na_v1.8 contributing effective modest depolarizations. SIGNIFICANCE STATEMENT Cannabidiol inhibit pain rodent models, this effect unknown. describe ability nociceptive dorsal root ganglia analyze voltage-dependent channels. find interacts manner suggesting particularly states dominate overall inactivation for small maintained resting potential. results suggest exert part directly nociceptors strategy identifying compounds bind selectively developing analgesics.

Language: Английский

---

Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy

British Journal of Pharmacology, Journal Year: 2021, Volume and Issue: 178(24), P. 4826 - 4841

Published: Aug. 12, 2021

Background and Purpose Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) Dravet syndrome. Unregulated artisanal cannabis‐based products children intractable epilepsies often contain relatively low doses CBD but are enriched in other phytocannabinoids. This raises the possibility that cannabis constituents might have anticonvulsant properties. Experimental Approach We Scn1a +/− mouse model syndrome investigate plant phytocannabinoids effects against hyperthermia‐induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined spontaneous seizures survival mice electroshock seizure models. Pharmacological CBGA were surveyed across multiple drug targets. Key Results initial screen identified three novel properties: CBGA, cannabidivarinic (CBDVA) cannabigerovarinic (CBGVA). potent potentiated clobazam seizures, MES threshold test. However, proconvulsant 6‐Hz test a high dose increased frequency mice. found interact numerous epilepsy‐relevant targets including GPR55, TRPV1 channels GABA A receptors. Conclusion Implications These results suggest CBDVA CBGVA may contribute childhood epilepsy. Although these potential could be lead compounds development programmes, several liabilities would need overcome before is superseded another this class.

Language: Английский

---

Cannabis sativa CBD Extract Shows Promising Antibacterial Activity against Salmonella typhimurium and S. newington

Molecules, Journal Year: 2022, Volume and Issue: 27(9), P. 2669 - 2669

Published: April 21, 2022

Products derived from

Language: Английский

---

Neuroprotective potential of cannabidiol: Molecular mechanisms and clinical implications

Journal of Integrative Medicine, Journal Year: 2023, Volume and Issue: 21(3), P. 236 - 244

Published: March 18, 2023

Language: Английский

---