Silencing of the GluN1-NMDA Glutamate Receptor Subunit by Intranasal siRNA Increases the Latency Time for Seizures in the Pilocarpine Rodent Model of Epilepsy.

Temporal lobe epilepsy (TLE) is the most prevalent and treatment-refractory type of epilepsy. Among the different mechanisms associated with epileptogenesis, overstimulation of glutamatergic neurotransmission has been associated with the onset and progression of seizures in TLE. Experimental evidence indicates that blocking the N-methyl-D-aspartate (NMDA) receptor or suppressing the expression of its subunit, mainly GluN1, may be effective in preventing epileptic seizures. Small interfering RNA (siRNA) has received attention as a potential therapeutic tool due to the inhibition of gene expression in some diseases. The present work evaluated the potential silencing effect of intranasal administration of an siRNA conjugate against the GluN1 subunit in animals submitted to the pilocarpine model of epilepsy. The results showed that the siRNA conjugate transfection system silences the GluN1 subunit in the hippocampus of rats when administered intranasally. As demonstrated by the RT-qPCR and Western blotting approaches, the silencing of GluN1 was specific for this subunit without affecting the amount of mRNA for other subunits. Silencing increased the latency time for the first tonic-clonic seizure when compared to controls. The overlapping of findings and the validation of the intranasal route as a pharmacological route of siRNA targeting the GluN1 subunit give the work a significant biotechnological interest.

Neonatal maternal deprivation facilitates the expression of a panic-like escape behavior in adult rats.

A wealth of evidence associates disruptions of the parent-infant relationship (e.g. childhood parental loss or parental neglect) with the later appearance of panic disorder. In rodents, neonatal maternal separation and maternal deprivation (MD) are reported to increase the expression of anxiety-related defensive responses in adult animals. However, little is known about the long-term consequences of these early-life stressors in animal models of panic. We here investigated the effects of a single 24 h-episode of MD on post-natal day 11 (PND 11) in adult male Wistar rats submitted to two animal models that associate escape expression with panic attacks: the elevated T-maze and exposure to severe hypoxia (7% O2). We also investigated the involvement of serotonin (5-HT) in the observed changes. Although neonatal MD did not affect the behavioral responses measured in the elevated T-maze, it facilitated the expression of escape during hypoxia exposure, indicating a panicogenic-like effect. Pre-test administration of the 5-HT synthesis inhibitor, para-chlorophenylalanine (PCPA; 4 daily injections of 100 mg/kg) facilitated escape attempts in non-deprived animals during the hypoxia challenge, but did not interfere with the expression of this behavior in maternally-deprived rats. The levels of 5-HT1A receptors in key panic- and anxiety-associated areas, the dorsal periaqueductal gray and amygdala, respectively, were not different between previously deprived and non-deprived animals. Plasma corticosterone levels were significantly increased by hypoxia exposure, independently of the animals' previous stress condition or PCPA administration. Therefore, MD on PND 11 predisposes the adult animal to the panic-evoking effects of severe hypoxia, a stimulus also reported to induce panic attacks in humans. The lack of PCPA effect on the pro-escape consequence of MD may be indicative that 5-HT signaling is impaired in the stressed animal.

Anxiety: a systematic review of neurobiology, traditional pharmaceuticals and novel alternatives from medicinal plants.

Pathologic anxiety is a disproportional reaction of individuals to anticipation or misinterpretation of a potential danger, which affects individual social and personal life. Despite the advances already accomplished, further studies are still necessary in order to understand the mechanisms involved in anxiety. These may provide more effective and safer treatments to aid in the control of anxiety and improve patient quality of life. In this work, we review the current issue about anxiety disorders, covering general aspects such as basic epidemiology and classification, an overview of the pharmacological treatments employed and the current search for natural anxiolytics. Also, a compilation of data investigating the neurobiology that underlies anxiety disorders and a brief discussion evolving the most usual animal experimental models to study anxiety is presented.