T-817MA, but Not Haloperidol and Risperidone, Restores Parvalbumin-Positive γ-Aminobutyric Acid Neurons in the Prefrontal Cortex and Hippocampus of Rats Transiently Exposed to MK-801 at the Neonatal Period
The number of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons is decreased in the brain of rats transiently exposed to MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in the neonatal stage (Uehara et al. (2012)). T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate] is a neuroprotective agent synthesized for the treatment of psychiatric disorders characterized by cognitive disturbances, such as dementia. We herein sought to determine whether T-817MA, haloperidol (HPD), or risperidone (RPD) would ameliorate the decrease in the number of PV-positive GABA neurons in the medial prefrontal cortex (mPFC) and hippocampus of the model animals. Rats were treated with MK-801 (0.2？mg/kg/day) or vehicle on postnatal days (PD) 7–10, and the number of PV-positive neurons in the mPFC and hippocampus were measured on PDs 63. T-817MA (20？mg/kg), HPD (1？mg/kg), or RPD (1？mg/kg) were administered during PDs 49–62. Fourteen-day administration of T-817MA reversed the decrease in the number of PV-positive neurons in the above brain regions of rats given MK-801, whereas HPD and RPD were ineffective. These results indicate that T-817MA provides a novel pharmacologic strategy to enhance cognitive function in patients with schizophrenia. 1. Introduction Schizophrenia is a complex and severe disorder, which affects approximately 1% of general population [1, 2]. Patients with the illness manifest positive symptoms (e.g., delusions, hallucinations, thought disorder) and negative symptoms (e.g., anhedonia, blunted affect, social withdrawal), as well as disturbances in a range of cognitive domains, such as several types of memory, attention/information processing, executive functions, and verbal fluency [2]. The clinical course of schizophrenia is characterized by episodic positive symptoms and progressive negative and cognitive symptoms. The onset of illness is generally in the late adolescence or early adulthood, which is preceded by prodromal symptoms, including nonspecific mood symptoms, mild psychotic symptoms, cognitive impairment, and social withdrawal [3]. About one-third is resistant to treatment with existing antipsychotic drugs [4]. Schizophrenia is considered as a neurodevelopmental disorder [5, 6]. Progressive pathophysiological processes possibly begin in the prodromal stage and continue after the onset of the illness [3, 7, 8]. Apoptosis (programmed cell death) may play a role in this process that leads to neurodegeneration. The vulnerability of neurons to proapoptotic insults (proapoptotic triggers) could produce selective
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