Improvement of cognitive dysfunction by a novel phosphodiesterase type 5 inhibitor, Tadalafil.

There is substantial evidence for the modulatory role of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterases (PDEs) in memory and synaptic plasticity, and an increase in intracellular cGMP facilitates these processes. The present study was aimed at the neuropharmacological investigations of tadalafil (TAD 5, 10, and 20 mg/kg, p.o.) and further involvement of nitric oxide (NO)-cGMP in its effects. The effects of tadalafil and its combination with NG -nitro-L-arginine methyl ester (L-NAME) were investigated in scopolamine- and diabetes-induced cognitive dysfunction using elevated plus maze (EPM) and object recognition (ORT) tests. The results of EPM revealed that the scopolamine- and diabetes-induced learning and memory deficit was dose dependently attenuated after administration of TAD (TAD 10 and 20 mg/kg, p.o.) in both paradigms studied. Administration of L-NAME (20 mg/kg) aggravated scopolamine- and diabetes-induced learning and memory deficit. Co-administration of L-NAME (20 mg/kg) after TAD (20 mg/kg) produced significant increase in cognitive performance as compared to scopolamine- and diabetic- control group. This showed that L-NAME (20 mg/kg) aggravated scopolamine- and diabetes-induced learning and memory deficit was significantly reversed by TAD (20 mg/kg). The results of the present study revealed that tadalafil by inhibiting PDE5 possibly elevated the cGMP level that through a diversity of its substrates produced neuropharmacological effects in cognitive dysfunction.

Therapeutic potential of metabotropic glutamate receptor 4-positive allosteric modulator TAS-4 in rodent models of movement disorders.

Parkinson's disease (PD) is a very serious neurological disorder, and current methods of treatment fail to achieve long-term control. Previous studies suggest that stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of Parkinson's disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. In the present study, we describe the pharmacological characterization of an mGluR4 PAM, N-(2, 4-dichlorophenyl) pyridine-2-carboxamide (TAS-4), in several rodent PD models. TAS-4 is a potent and selective mGluR4 PAM of the human mGluR4 receptor (EC50- 287.8nM). TAS-4 showed efficacy alone or when administered in combination with l-DOPA. When administered alone, TAS-4 exhibited efficacy in reversing haloperidol-induced catalepsy. In addition, acute TAS-4 dose-dependently potentiated contralateral turning behavior induced by a threshold dose of l-3,4-dihydroxyphenylalanine (l-DOPA, 4mg/kg i.p.), a classical test for antiparkinson drug screening. Subchronic (28days, twice a day) TAS-4 (10mg/kg i.p.)+l-DOPA (4mg/kg i.p.) did not induce sensitization to turning behavior or abnormal involuntary movements during the course of treatment. Moreover, subchronic administration of a fully effective dose of l-DOPA (8mg/kg i.p.) significantly induces sensitization to turning behavior or abnormal involuntary movements. Results showed that TAS-4, in association with a low dose of l-DOPA, displayed antiparkinsonian activity similar to that produced by a full dose of l-DOPA without exacerbating abnormal motor side effects.

NS-1: a novel partial peroxisome proliferator-activated receptor γ agonist to improve insulin sensitivity and metabolic profile.

Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. We characterized the pharmacological profiles of NS-1 chemically known as (5Z)-5-[4-hydroxy-3-methoxy-phenyl) methylene] thiazolidine-2, 4-dione), as a selective partial activator of PPARγ. In transient transactivation assay in NIH3T3 cells, NS-1 showed a partial activation against human PPARγ with an EC (50) of 0.91 µM without activating human PPARα and PPARδ. In adipocyte differentiation assay, NS-1 induced adipocyte differentiation, which was ~25-fold weaker inducer of GPDH activities than pioglitazone and also showed weak adipogenic activity in C3H10T1/2 pluripotent stem cells using Oil Red O staining. NS-1 showed good in vivo pharmacokinetic profiles in C57BL/6J mice at 30 mg/kg oral dose with Cmax-26 µM, terminal elimination half-life- 2.5h and bioavailability of 85%. Furthermore, NS-1 significantly improved hyperglycemia and insulin resistance in DIO animals when orally administered at a dose of 30 mg/kg/day for 45 days without significant weight gain. Overall, these studies suggest that NS-1 improves insulin resistance in such animal models through activation of PPARγ-mediated transcriptional activity and that it would be a new therapeutic candidate with potential for the treatment of type 2 diabetic patients.

Protective effect of aqueous extract of Spinacia oleracea leaves in experimental paradigms of inflammatory bowel disease.

The present study was aimed to assess the protective effect of aqueous extract of Spinacia oleracea leaves (AESO 250, 500, and 1,000 mg/kg, p.o.) in inflammatory bowel disease using acetic acid- and ethanol-induced colitis in mice and indomethacin-induced enterocolitis in rats. The preliminary phytochemical analysis and further high performance thin layer chromatographic (HPTLC) analysis and phytochemical tests of HPTLC bands confirmed the presence of flavonoids and tannins in AESO. In acute oral toxicity study, administration of AESO (5,000 mg/kg, p.o.) did not show any sign of toxicity and mortality. The treatment with AESO significantly increased body weight, decreased diarrhea with bloody stools, increased blood hemoglobin and plasma total protein, and decreased serum and ileum or colon malondialdehyde content and attenuated the extent of lesions and ameliorated the histological injury of mucosa in all paradigms. The most prominent effects were evident for AESO 1,000 mg/kg. The results of the present study revealed that AESO was effective in attenuating almost all the symptoms of IBD in experimental paradigms. The effect might be due to the antioxidant activity of the flavonoids present in the AESO.