Antipsychotic-like effects of a novel phosphodiesterase 10A inhibitor MT-3014 in rats.

Phosphodiesterase (PDE) 10A is an attractive therapeutic target for schizophrenia. Here, we investigated the antipsychotic-like effects of a novel PDE10A inhibitor, 1-({2-(7-fluoro-3-methylquinoxalin-2-yl)-5-[(3R)-3-fluoropyrrolidin-1-yl]pyrazolo[1,5-α]pyrimidin-7-yl}amino)-2-methylpropan-2-ol hydrochloride (MT-3014) in rats. MT-3014 showed a potent and selective inhibitory effect against PDE10A (IC50 = 0.357 nmol/L). Oral administration of MT-3014 (1.0-10 mg/kg) significantly increased the levels of cAMP, cGMP and cAMP response element-binding protein (CREB) phosphorylation in the rat striatum. MT-3014 decreased MK-801 (0.075 mg/kg)-induced hyperactivity (ED50 = 0.30 mg/kg) in a dose-dependent manner, although it decreased spontaneous locomotion in control rats (ED50 = 0.48 mg/kg); its effects were equivalent to those of risperidone. MT-3014 (0.3-3.0 mg/kg and 0.2 mg/kg) attenuated MK-801-induced prepulse inhibition deficits and cognitive deficits in rats, respectively, whereas risperidone attenuated MK-801-induced prepulse inhibition at only a high dose and failed to improve MK-801-induced cognitive deficits. Similar to risperidone (ID50 = 0.63 mg/kg), MT-3014 suppressed the conditioned avoidance response (ID50 = 0.32 mg/kg). Interestingly, MT-3014 did not elicit catalepsy and plasma prolactin increases at high doses. Furthermore, it also did not affect body weight. A positron emission tomography study using [11C]IMA107 showed a plasma concentration-dependent increase in brain PDE10A occupancy after oral administration of MT-3014 within the pharmacological dose range in rats. Brain PDE10A occupancy corresponding to the ID50 value in the conditioned avoidance response was approximately 60%, predicting the target occupancy in patients with schizophrenia. These results suggest that MT-3014 may be a novel antipsychotic drug, which is expected to have additional effects on cognitive impairment, without the prominent side effects associated with current atypical antipsychotics.

Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis.

A growing body of evidence suggests the involvement of inflammatory processes in the pathophysiology of schizophrenia. Four- to 8-week exposure to cuprizone, a copper chelator, causes robust demyelination and has been used to build a model for multiple sclerosis. In contrast, we report here the effects of 1-week cuprizone exposure in mice. This short-term cuprizone exposure elicits behavioral changes that include augmented responsiveness to methamphetamine and phencyclidine, as well as impaired working memory. The cellular effects of 1-week cuprizone exposure differ substantially from the longer-term exposure; perturbation of astrocytes and microglia is induced without any sign of demyelination. Furthermore, the proinflammatory cytokine interleukin-6 was significantly up-regulated in glial fibrillary acidic protein (GFAP)-positive cells. We propose that this cuprizone short-term exposure may offer a model to study some aspects of biology relevant to schizophrenia and related conditions.

Silencing of insulin-like growth factor-binding protein-2 in human glioblastoma cells reduces both invasiveness and expression of progression-associated gene CD24.

Glioblastoma multiforme (GBM) is a malignant brain tumor characterized by rapid growth and extensive invasiveness. Overexpression of insulin-like growth factor-binding protein-2 (IGFBP-2) has been reported in GBM. However, it remains to be determined how IGFBP-2 is involved in the progression of GBM. We utilized short hairpin-RNA (shRNA) expression retroviral vectors to inactivate the IGFBP-2 gene permanently in two human GBM cell lines, U251 and YKG-1. The stable knockdown of IGFBP-2 resulted in decreased invasiveness, decreased saturation density of the cells in vitro, and decreased tumorigenicity in nude mice. Transcriptional profiling of both lines revealed several genes that were significantly down-regulated by inactivation of IGFBP-2. One such gene was CD24, which has been implicated in progression of various cancers. Indeed, CD24 was expressed in most GBM cases and the inactivation of CD24 in GBM cells suppressed cellular invasiveness, as was the case for IGFBP-2. Forced overexpression of CD24 led to increased invasiveness of both IGFBP-2-inactivated GBM cell lines and also A172, a human GBM cell line with low endogenous CD24. Further supporting the inter-relationship between IGFBP-2 and CD24, knockdown of IGFBP-2 suppressed the CD24 promoter activity. Moreover, both CD24 promoter activity and in vitro invasiveness were restored in knockdown cells by transfection with an IGFBP-2 expression plasmid. These results indicate that CD24 is modulated by IGFBP-2 and contributes to IGFBP-2-enhanced invasiveness of GBM cells.