Inhibition of protease-activated receptor 1 ameliorates behavioral deficits and restores hippocampal synaptic plasticity in a rat model of status epilepticus.

The blood-brain barrier (BBB) is a unique structure that controls substances exchange between the systemic circulation and the brain. Disruption of its integrity contributes to the development and progression of a variety of brain disorders including stroke, epilepsy and neurodegenerative diseases. It was shown that intracerebral thrombin level substantially increases following status epilepticus (SE). Inhibition of protease-activated receptor 1 (PAR1), the major thrombin receptor in the brain, produces an anti-epileptogenic and neuroprotective effects in an experimental model of temporal lobe epilepsy (TLE). Since serine proteases and PAR1 are implicated in the synaptic plasticity and memory formation, the aim of the present study was to elucidate the involvement of PAR1 in synaptic plasticity and behavior deficits following SE. Using lithium-pilocarpine model of TLE, we demonstrate that inhibition of PAR1 rescues SE-induced synaptic plasticity deficits in CA1 region of hippocampus. Although treatment with PAR1 antagonist does not ameliorate spatial learning deficits, it attenuates anxiolytic-like behavior in experimental rats after SE. Taken together; our data suggest an important role of PAR1 in SE-induced synaptic and behavioral alterations and provide a new insight into cellular mechanisms underlying behavioral impairments associated with epilepsy.

Effects of protease-activated receptor 1 inhibition on anxiety and fear following status epilepticus.

Protease-activated receptor 1 (PAR1) is an important contributor to the pathogenesis of a variety of brain disorders associated with a risk of epilepsy development. Using the lithium-pilocarpine model of temporal lobe epilepsy (TLE), we recently showed that inhibition of this receptor during the first ten days after pilocarpine-induced status epilepticus (SE) results in substantial anti-epileptogenic and neuroprotective effects. As PAR1 is expressed in the central nervous system regions of importance for processing emotional reactions, including amygdala and hippocampus, and TLE is frequently associated with a chronic alteration of the functions of these regions, we tested the hypothesis that PAR1 inhibition could modulate emotionally driven behavioral responses of rats experiencing SE. We showed that SE induces a chronic decrease in the animals' anxiety-related behavior and an increase of locomotor activity. PAR1 inhibition after SE abolished the alteration of the anxiety level but does not affect the increase of locomotor activity in the open field and elevated plus maze tests. Moreover, while PAR1 inhibition produces an impairment of memory recall in the context fear conditioning paradigm in the control group, it substantially improves contextual and cued fear learning in rats experiencing SE. These data suggest that PAR1-dependent signaling is involved in the mechanisms underlying emotional disorders in epilepsy.