ИСТИНА

Proline-containig dipeptide Noopept (NP) is a structural analog of piracetam, one of the first generation nootropics. Like piracetam, NP demonstrates wide spectrum of cognition improvment as well as neuroprotective properties in vivo and in vitro although at much lower doses. Its positive effect was also confirmed in patients with mild cognitive impairment of cerebrovascular and traumatic origin, in animal models of brain ischemia, Alzheimer and Parkinson diseases (Ostrovskaya et al., 2008; Jia et al., 2011). Although the effectiveness of NP was shown in a number of studies, the mechanism of its action, cellular targets as well as affected signaling pathways are still poorly understood. Our previous results demonstrated that NP significantly increased action potential (AP) frequency in stratum radiatum (SR) interneurons and the frequency of AP-dependent IPSC in pyramidal cells. In this study, we continued this line performing direct measurements of neuronal intracellular calcium in hippocampal organotypic slices from postnatal (p6) rats. We showed for the first time that NP activated neuronal calcium dynamics in regional specific manner. It selectively increased the frequency of Ca transients inhippocampal neurons located in SR without significant changes in pyramidal layer (SP) and basal level of Ca in all investigated neurons. The amplitude and duration of transients as well as the background level of intracellular calcium was not subject to significant changes during the NP application. Taking into account layer specificity of neuronal distribution in hippocampus we conclude that NP selectively changes intracellular calcium activity in SR interneurons without significant changes in SP neurons - preferentially pyramidal neurons. The most straightforward assumption is that NP affects glutamate or cholinergic transmission. Besides the fact that both types of synapses are abundant in CA1, they also have Ca-permeable postsynaptic targets selectively expressed in SR interneuron: Ca-permeable AMPAR (Buldakova et al.,2007) and alpha 7-containing nicotinic AChR (Khiroug et al., 2003). Selective stimulation of cholinergic transmission may explain compensatory effect of NP in experimental models of memory loss (Belnik et al.,2007) and augmentation of response to exogenous ACh (Ostrovskaya et al., 2001). Involvement of cholinergic transmission is supported by our preliminary electrophysiological results demonstrating the block of NP effect on IPSCs in pyramidal neurons by methyllycaconitine -selective antagonists of alpha 7-containing nicotinic AChR. Additional experiments are required to elucidate the target of NP effect.