piperidines and Toxoplasmosis

Toxoplasmosis is an infectious disease caused by the intracellular parasite Toxoplasma gondii that harms the brain and increases the risk of epilepsy acquisition. It is well known that cannabinoid (CB) signaling is activated following brain insults and protects the neurons from excitotoxicity and inflammation. We examined the role of CB neurotransmission in the proconvulsant effect of Toxoplasmosis in mice. Toxoplasmosis was established in mice by intraperitoneal injection of T. gondii cysts. The mice with acute and/or chronic Toxoplasma infection were pretreated (through intracerebroventricular injection) with CB1 and CB2 receptor agonists (ACEA and HU308) and antagonists (AM251 and AM630), as well as JZL184 (the irreversible inhibitor of mono acyl glycerol lipase, enzyme degrading the endogenous cannabinoid 2-Acyl glycerol). The seizure threshold was then measured by tail vein infusion of pentylenetetrazole. In healthy uninfected mice JZL184, ACEA, and AM630 increased the seizure threshold in a dose-dependent manner, whereas AM251 and HU308 showed dose-dependent proconvulsant effect. Mice with acute and/or chronic infection had a substantial lower seizure threshold than the uninfected mice. JZL 184, ACEA and AM630 inhibited proconvulsant effect of Toxoplasmosis, while AM251 and HU308 intensified proconvulsant effect of Toxoplasmosis. CB receptors play a role in proconvulsant effect of Toxoplasmosis in mice.

Topics: Animals; Benzodioxoles; Cannabinoids; Disease Models, Animal; Indoles; Male; Mice; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Toxoplasma; Toxoplasmosis

Topics: Animals; Cell Line; Coccidiosis; Embryonic Development; Female; Hep G2 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Naphthalenes; Neospora; Piperidines; Pregnancy; Pregnancy Complications; Protein Kinases; Pyrazoles; Pyrimidines; Quinolines; Toxoplasma; Toxoplasmosis; Zebrafish

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Topics: Animals; Drug Resistance; Focal Adhesion Kinase 2; Humans; Naphthalenes; Piperidines; Protein Kinase Inhibitors; Protozoan Proteins; Pyrazoles; Toxoplasma; Toxoplasmosis

Toxoplasma gondii is a unicellular parasite that causes severe brain and eye disease. Current drugs for T. gondii are limited by toxicity. Bumped kinase inhibitors (BKIs) selectively inhibit calcium-dependent protein kinases of the apicomplexan pathogens T. gondii, cryptosporidia, and plasmodia. A lead anti-Toxoplasma BKI, 1294, has been developed to be metabolically stable and orally bioavailable. Herein, we demonstrate the oral efficacy of 1294 against toxoplasmosis in vivo.

Topics: Animals; Antiprotozoal Agents; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred BALB C; Naphthalenes; Piperidines; Protein Kinase Inhibitors; Protein Kinases; Protozoan Proteins; Pyrazoles; Toxoplasma; Toxoplasmosis