Bupivacaine is a BK SK, Kv1, Kv3, TASK-2 K Channel and voltage-gated Na channel blocker used as an anesthetic. It maybe neurotoxic at high does, inducing apoptosis in neuroblastoma cells. It acts by binding to the intracellular portion of voltage-gated sodium channels and blocking sodium influx into nerve cells.
A-971432 is a sphingosine-1-phosphate receptor 5 (S1P5) agonist that is selective for S1P5 over S1P1 and S1P3 (IC50s = 0.006, 0.362, and >10 µM, respectively). It inhibits forskolin-induced cAMP production in CHO cells expressing S1P5 (EC50 = 4.1 nM). A-971432 (1 µM) increases electrical resistance of hCMEC D3 cells in an in vitro blood-brain barrier model, indicating enhanced barrier integrity, and attenuates blood-brain barrier leakage in an R6 2 transgenic mouse model of Huntington’s disease when administered at a dose of 0.1 mg kg.[1] [2] A-971432 (0.1 mg kg per day, i.p.) decreases the number of errors made in a horizontal ladder task and increases latency to fall in the rotarod test in R6 2 mice. It also increases spontaneous alternation in the t-maze in aged mice when administered at a dose of 0.1 mg kg.[1] References [1].Hobson, A.D., Harris, C.M., van der Kam, E.L., et al. Discovery of A-971432, an orally bioavailable selective sphingosine-1-phosphate receptor 5 (S1P5) agonist for the potential treatment of neurodegenerative disorders. J. Med. Chem. 58(23), 9154-9170 (2015).[2]. Di Pardo, A., Castaldo, S., Amico, E., et al. Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington’s disease. Hum. Mol. Genet. 27(14), 2490-2501 (2018).
PF-04449613 is a phosphodiesterase 9A (PDE9A) inhibitor (IC50= 22 nM).1It is selective for PDE9A over PDE1C (IC50= >1,000 nM), as well as over a variety of other PDEs, inhibiting PDE2-8, -10, and -11 activity by less than 30% in a panel of enzymes, ion channels, and transporters at 1 μM but does inhibit the human dopamine transporter (DAT; Ki= 293 nM). PF-04449613 (0.1-100 mg kg, s.c.) increases cerebrospinal fluid (CSF) levels of cyclic GMP (cGMP) in rats. Subcutaneous administration of PF-04449613 (10 mg kg) increases the rate of dendritic spine formation and elimination in mouse primary motor cortex pyramidal neuronsin vivo.2It increases the average running speed of mice in an accelerating rotarod task, indicating improved motor learning, at the same dose. 1.Claffey, M.M., Helal, C.J., Verhoest, P.R., et al.Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitorsJ. Med. Chem.55(21)9055-9068(2012) 2.Lai, B., Li, M., Hu, A., et al.The phosphodiesterase 9 inhibitor PF-04449613 promotes dendritic spine formation and performance improvement after motor learningDev. Neurobiol.78(9)859-872(2018)
Pyrithiamine is the pyridine analog of thiamine that prevents growth of organisms that require intact thiamine. [1] It inhibits the growth of bacterial and fungal species at a pyrithiamine:thiamine ratio of 10:1 in growth media and induces symptoms of thiamine deficiency in mice at a dietary ratio of 3:1. These effects are reversible with addition of sufficient thiamine in all species. Pyrithiamine inhibits the formation of cocarboxylase from thiamine in chicken blood in a dose-dependent manner. [2] It has been used to induce thiamine deficiency in various disease models, including rat models of alcoholism and diencephalic amnesia, to study the effects of thiamine deficiency on disease pathology.[3] [4] Reference:[1]. Woolley, D.W., and White, A.G.C. Selective reversible inhibition of microbial growth with pyrithiamine. J. Exp. Med. 78(6), 489-497 (1943).[2]. Woolley, D.W. An enzymatic study of the mode of action of pyrithiamine (neopyrithiamine). J. Biol. Chem. 191(1), 43-54 (1951).[3]. Vetreno, R.P., Anzalone, S.J., and Savage, L.M. Impaired, spared, and enhanced ACh efflux across the hippocampus and striatum in diencephalic amnesia is dependent on task demands. Neurobiol. Learn Mem. 90(1), 237-244 (2008).[4]. Zahr, N.M., Sullivan, E.V., Rohlfing, T., et al. Concomitants of alcoholism: Differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo. Psychopharmacology (Berl) 233(14), 2675-2686 (2016).