The new iminothiadiazole derivative VP1.14 ameliorates hippocampal damage after an excitotoxic injury

Abstract

J. Neurochem. (2012) 122, 1193–1202. Abstract Increased levels of glutamate causing excitotoxic damage accompany many neurological disorders. A well‐characterized model of excitotoxic damage involves administration of kainic acid (KA), which causes limbic seizure activity and subsequent neuronal death, particularly in the CA1 and CA3 areas of the hippocampus. Inhibition of the enzyme glycogen synthase kinase‐3 (GSK‐3) and cAMP levels might play an important role in neuroprotection. As intracellular cAMP levels depend, in part, on the activity of the phosphodiesterase enzymes (PDEs), these enzymes have recently emerged as potential therapeutic targets for the treatment of several diseases. In previous works, we have shown a potent anti‐inflammatory and neuroprotective effect of GSK‐3 inhibition in a model of excitotoxicity, as well as a reduction of nigrostriatal dopaminergic neuronal cell death after phosphodiesterase 7 inhibition, which leads to an increase in cAMP levels. This study was undertaken to determine whether simultaneous inhibition of GSK‐3 and PDE‐7 by a novel 5‐imino‐1,2,4‐thiadiazole compound, named VP1.14, could prevent the massive neuronal loss in the hippocampus evoked by intrahippocampal injection of KA. Here, we show that rats treated with VP1.14 showed a reduced inflammatory response after KA injection, and exhibited a significant reduction in pyramidal cell loss in the CA1 and CA3 areas of the hippocampus. Studies with hippocampal HT22 cells in vitro also showed a clear neuroprotective effect of VP1.14 and an anti‐inflammatory effect shown by a decrease in the nitrite liberation and in the expression of pro‐inflammatory cytokines by primary cultures of astrocytes treated with lipopolysaccharide.

Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice

“…Importantly, depletion of PDE7B levels by lentiviral delivery of PDE7 shRNA significantly ameliorates the motor impairment subsequent to dopaminergic cell loss. Previous results from our group demonstrate that chemical inhibition of PDE7 trigger neuroprotection and diminish neuroinflammation in different models of brain diseases, including PD (Castano et al, 2009;Morales-Garcia et al, 2011;Redondo et al, 2012;Susin et al, 2012). Other authors have shown a Fig.…”

“…As commented previously, our group has been the first to show a potent neuroprotective and anti-inflammatory effect of different PDE7 chemical inhibitors in different animal models of PD (Morales-Garcia et al, 2011;Susin et al, 2012), suggesting that this enzyme could be a promising new therapeutic target for the treatment of this devastating disorder. In this work, we show that lentiviral-mediated delivery of PDE7B small hairpin RNA (shRNA) into the SNpc of adult mice protected 80% of dopaminergic neurons and decreased glial activation after an intranigral injection of lipopolysaccharide (LPS) or 6-hydroxydopamine (6-OHDA).…”

“…Given the important role of cAMP in the brain, specific inhibitors of PDEs are being analyzed as possible therapeutic targets for the treatment of different brain diseases (Garcia-Osta et al, 2012;Menniti et al, 2006;Sharma et al, 2013). During the last years, we have shown that different inhibitors of PDE7 are potent neuroprotective and anti-inflammatory agents in several animal models of neurodegenerative disorders, including PD (Castano et al, 2009;MoralesGarcia et al, 2011;Redondo et al, 2012;Susin et al, 2012).…”

Quinazoline pharmacophore in therapeutic medicine

“…Mono-substitution on position 6 of quinazoline core was crucial for effective inhibition wherein substituents of priority which possessed tight package and hydrophobicity are: Methoxy (23b, IC50 = 0.23 µM), methyl (23c, 0.10 µM), chloro (23d, 0.019 µM), thiomethyl (23f, 0.031 µM), and cyano (23p, 0.090 µM) functionalities (Takase et al, 1994) as shown in Figure 12. Administration of 3-substitutedquinazolin-2,4-dithione as optimized PDE7 inhibitor improved brain damage and enhanced behavioral aftermath in a permanent middle cerebral artery obstruction (pMCAO) stroke model (Redondo et al, 2012;Susín et al, 2012). Sánchez et al (2013) reported the inhibitory potencies of quinazoline-4-thione 24 at submicromolar levels against the catalytic domain of PDE7.…”

Crosstalk between Phosphodiesterase 7 and Glycogen Synthase Kinase-3: Two Relevant Therapeutic Targets for Neurological Disorders

“…The concentration of the different compounds was chosen based on their effectiveness in different previously published works. 8,22,31,46,47 Previously to the treatment with the test compounds, some plates were also preincubated with the PKA inhibitor H-89 (20 μM, BIOMOL Research Laboratories). After treatments, cells were processed for Western blot analysis, immunocytochemistry, or nitrite release.…”