Neuroprotective effects of platinum nanoparticle-based microreactors in bicuculline-induced seizures.

Epilepsy designates a group of chronic brain disorders, characterized by the recurrence of hypersynchronous, repetitive activity, of neuronal clusters. Epileptic seizures are the hallmark of epilepsy. The primary goal of epilepsy treatment is to eliminate seizures with minimal side effects. Nevertheless, approximately 30% of patients do not respond to the available drugs. An imbalance between excitatory/inhibitory neurotransmission, that leads to excitotoxicity, seizures, and cell death, has been proposed as an important mechanism regarding epileptogenesis. Recently, it has been shown that microreactors composed of platinum nanoparticles (Pt-NP) and glutamate dehydrogenase possess in vitro and in vivo activity against excitotoxicity. This study investigates the in vivo effects of these microreactors in an animal model of epilepsy induced by the administration of the GABAergic antagonist bicuculline. Male Wistar rats were administered intracerebroventricularly (i.c.v.) with the microreactors or saline and, five days later, injected with bicuculline or saline. Seizure severity was evaluated in an open field. Thirty min after behavioral measurements, animals were euthanized, and their brains processed for neurodegeneration evaluation and for neurogenesis. Treatment with the microreactors significantly increased the time taken for the onset of seizures and for the first tonic-clonic seizure, when compared to the bicuculline group that did not receive the microreactor. The administration of the microreactors also increased the time spent in total exploration and grooming. Treatment with the microreactors decreased bicuculline-induced neurodegeneration and increased neurogenesis in the dorsal and ventral hippocampus. These observations suggest that treatment with Pt-NP-based microreactors attenuates the behavioral and neurobiological consequences of epileptiform seizure activity.

Platinum nanoparticle-based microreactors protect against the behavioral and neurobiological consequences of chronic stress exposure.

Excitotoxicity is described as the exacerbated activation of glutamate AMPA and NMDA receptors that leads to neuronal damage, and ultimately to cell death. Astrocytes are responsible for the clearance of 80-90% of synaptically released glutamate, preventing excitotoxicity. Chronic stress renders neurons vulnerable to excitotoxicity and has been associated to neuropsychiatric disorders, i.e., anxiety. Microreactors containing platinum nanoparticles (Pt-NP) and glutamate dehydrogenase have shown in vitro activity against excitotoxicity. The purpose of the present study was to investigate the in vivo effects of these microreactors on the behavioral and neurobiological effects of chronic stress exposure. Rats were either unstressed or exposed for 2 weeks to an unpredictable chronic mild stress paradigm (UCMS), administered intra-ventral hippocampus with the microreactors (with or without the blockage of astrocyte functioning), and seven days later tested in the elevated T-maze (ETM; Experiment 1). The ETM allows the measurement of two defensive responses, avoidance and escape, in terms of psychopathology respectively related to generalized anxiety and panic disorder. Locomotor activity in an open field was also measured. Since previous evidence shows that stress inhibits adult neurogenesis, we evaluated the effects of the different treatments on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the dorsal and ventral hippocampus (Experiment 2). Results showed that UCMS induces anxiogenic effects, increases locomotion, and decreases the number of DCX cells in the dorsal and ventral hippocampus, effects that were counteracted by microreactor administration. This is the first study to demonstrate the in vivo efficacy of Pt-NP against the behavioral and neurobiological effects of chronic stress exposure.