10^th International Conference on Neuroscience and Neurochemistry February 27-28, 2017 Amsterdam, Netherlands

Nonlinear impacts on human brain for recovering of physiological and mental activity and for rehabilitation in extreme ambient conditions

In 2015, we theoretically substantiated the hypothesis that there is the intimate link between the complexity of neural connections, nonlinear dynamics of physiological processes in the brain and the nonlinear characteristics of sensory environmental cues. The impact throughout the person's life of visual and other sensory environmental cues of a complex spatiotemporal structure is necessary for normal maturation, development, and aging of the brain. The theory associates the development and maintenance of healthy structure and activity of the neural networks of the brain and retina with the complexity of visual and other signals of the environment affecting the person, with his life experience of nonlinear stimulation. Hence, the need to maintain healthy fractal dynamics during life, using the natural and the artificial fractal cues when the dynamics of the brain’s function is disordered, or when there is a simplification of environmental stimuli. The use of fractal stimulation and other nonlinear effects can promote recovery of the function of the brain and the retina including neurodegenerative diseases, acting through the reactivation of neuroplasticity. Nonlinear stimulation therapy in medicine must become an essential element of therapeutic strategies for activating neuroplasticity and enhance the effectiveness of the treatment of some pathological conditions: glaucoma, retinitis pigmentosa, Alzheimer's disease, Parkinson's disease, sleep disorders, and amblyopia. Technologies of nonlinear impacts may be applied in various other pathological conditions, which are accompanied by the simplification of a temporal pattern of the brain activity and the emergence of deterministic or stochastic dynamics of fluctuations of various physiological functions. For the recovery after brain injuries and strokes, it is possible to use nonlinear techniques of stimulation therapy in the offices (centers) on rehabilitation and psychological training. Application of non-linear technologies is also prospective in following areas: Gerontology- under normal physiological human aging, the loss of the memory and some other cognitive functions occurs. Nonlinear stimulation techniques may be useful for normalization and long-term preservation of cognitive functions and intelligence of older people, promoting mental longevity; sport- nonlinear stimulation techniques may be helpful for increasing and rapid recovery of mental and physical performance in severe physical or psychological stress in athletes and; work in the extreme environment- nonlinear stimulation techniques may be useful for restoration and enhancement of cognitive function, preservation of critical thinking in the extreme conditions of work and stress situations, including long-term space missions.

Eva Kudova has been working at Institute of Organic Chemistry and Biochemistry in Prague, Czech Academy of Sciences (IOCB) since 2002. She completed her PhD in 2009 at Charles University in Prague. Then, she spent two years in the lab of Douglas F Covey, Washington University School of Medicine in St. Louis, Missouri, USA.Her research interest includes Steroidal Chemistry. She has been working in the field of Steroidal Chemistry for more than 10 years. Her major avenue of investigation is “Design and synthesis of new neuroactive steroidal compounds and structure-activity relationship studies affording NMDARs ligands”. Also, she and her colleagues have proposed screening pipeline that should serve as a screening platform for neuroactive steroids targeting CNS diseases and showing neurosteroids’ drug-likeness.

Neuroactive steroids as neuroprotective agents

Neuroactive compounds are synthetic analogues of neurosteroids that are naturally synthesized in the nervous tissue from cholesterol or steroidal precursors from peripheral sources. The neuroprotective effect of neurosteroids or neuroactive steroids is supposed to be realized via rapid, non-genomic mechanism. Multiple studies have been already performed to demonstrate efficacy of neurosteroids in the treatment of various central and peripheral nervous system diseases (e.g. ischemia, seizures, neurodegeneration, etc.). However, the mechanisms of neuroprotective effect of neuroactive steroids remain unclear and accumulating evidence indicate that this process can be regulated in multi-target manner. Moreover, neuroprotection include mechanisms protecting against neuronal injury/damage or degeneration according to acute or chronic origin of pathological process. As such, research targeting design and development of neuroprotective steroids with therapeutic potential is extremely challenging. In the last decade, we have synthesized a library of neuroactive steroids that act as potent negative modulators of N-methyl-D-aspartate receptors (NMDARs) that play significant role in learning and memory. Also, we have shown that these compounds do exhibit strong neuroprotective effect in in vivo models. Currently, our main avenue of investigation is development of an in vitro multiplexed screening platform to identify molecules with strong neuroprotective effect. Therefore, we have developed a methodology for neuroprotective effect screening in the model of glutamate/NMDA-induced excitotoxicity on embryonic cortex neurons. We conclude that pretreatment with our neurosteroids significantly reduced acute NMDA/L-glutamic acid excitotoxicity mediated by Ca²⁺ entry and consequent ROS release and caspase-3 activation. Compounds 6 (IC₅₀=5.8 µM), 7 (IC₅₀=12.2 µM), 9 (IC₅₀=7.8 µM), 13 (IC₅₀=1.1 µM) and 16 (IC₅₀=8.2 µM) attenuated glutamate-induced Ca²⁺ entry more effectively than memantine (IC₅₀=18.9 µM). Moreover, compound 13 was more effective than MK-801 (IC₅₀=1.2 µM). This drop in Ca²⁺ level resulted in corresponding reactive oxygen species suppression and prevented glutamate-induced caspase-3 activation.