Based on the revealed data the chronic noise action increased the level of peroxidation of membranes phospholipids in MFB and the level of MDA and decreased content of α-T in the plasma and EM of experimental animals. The Y-maze test also revealed cognitive disorders in rats under the noise action. The results obtained indicate onto changes in the studied biochemical parameters and the cognitive function, so testify about the regulative effects of the α2-adrenoblockers under the conditions of the chronic noise.
The stress realization phenomenon is a nonspecific response of the central nervous system (CNS) to a stressor with several morphological and biochemical deviations including those characteristics to the oxidative stress.
The processes of free radicals’ production dysregulation led to oxidation intensity changes consistent with a shift in MDA level, one of the most common biomarkers of LPO. The enhanced level of MDA also indicates on abnormality in antioxidant defense mechanisms. Results of our investigations have shown that chronic noise increased level of MDA in the plasma of the 2nd group, which is an accepted marker for oxidative stress and development of pathology [3]. Meanwhile, we recorded the noticeable restorative effects of beditin and mesedin on the levels of MDA in respective groups. Low levels of MDA in plasma of these groups were caused by the α2-adrenoblockers, where effect of mesedin was the mostly expressed. The latter was evident by the 4th group rats’ lowest MDA level, compared with the 1st group after 7 and 60 days of noise action.
Based on the data in the plasma levels of MDA, we found significant difference after noise exposition. Indicators of oxidative stress can be detected in various body fluids or tissues [26]. MDA is a product of lipid peroxidation, which immediately reacts with biomolecules in the cells [27]. Its increase indicates intensified oxidative stress in erythrocytes membranes due to an excessive production of ROS by noise action.
Our data demonstrated expressed quantitative deviations of MDA level in the EM under the noise exposure in the 2ndgroup. Interestingly, the stress-realizing hormones action brings to structural transitions in EM proteins, along which the deformation of erythrocytes is [28]. Structural changes of EM can promote oxidation of proteins and phospholipids by becoming a target of ROS. It was also shown that stress hormones alter the oxygen transport properties of erythrocytes. Increased level of MDA followed by development of oxidative stress could be one of the pathophysiologic mechanisms of diseases [29].
As a protective measure we used α2-adrenoblockers, mesedin and beditin, to reduce noise-induced symptoms and show their possible preventive effect under the chronic acoustic stress conditions. Reduction of the noise impact by α2-adrenoblockers was expressed by less level of MDA in the EM, in the 3rd and the 4th groups. Low level of MDA in these groups was caused by regulatory properties of α2-adrenoblockers [12, 30] compared with the 1st group after 7, 30 and 60 days of noise exposure.
The cellular effects of oxidative stress are characterized by free radicals, including ROS, which affect the molecular components of the cell membrane spatially membrane lipids and disturb their biophysical properties. In this aspects a-T is of widely recognized antioxidant action and as a lipid-soluble molecule, scavenging its free radical in the cell membranes and protecting primarily poly unsaturated fatty acids (PUFA), highly susceptible to oxidative attack [31,32].
In the given study in the 2nd rats α-T level was reduced in the EM and plasma after 7 day of noise influence, compared to control. The oxidative damage was continued by chronic exposure of noise (after 30 and 60 day), which was expressed by intensive decreased level of α-tocopherol in the 2nd group rats. Based on our data, we can postulate, that harmful effect of noise decreased endogenous antioxidant defense because of gradually decreasing scavenging of the free radicals and thus, damaging the cells. In the antioxidant defense overwhelming the oxidative stress to the cellular components induce adaptive processes [33]. The data from our previous study also confirmed this fact and showed adaptation processes on the 30th day of the noise exposure․ However, α-T studies have shown that noise-induced reductions in tocopherol levels were not accompanied by the adaptation phase. The amount of tocopherol was gradually decreased bypassing adaptation․ A study of the effects of beditine and mesedin showed that oxidative stress was limited by using of these α2- adrenoblockers, which was expressed by a slight increase of α-T in the studded group, compared to the noise group. Contributing to α-T levels, α2- adrenoblockers protected PUFA in cell membranes from LPO and preserve the physical properties of the membranes [34]. Considering the biological effects specificity inhibited by α-T, it does not seem plausible that numerous effects can be mediated by uncontrolled LPO and so, counteracted by the antioxidant [35]. By protection of the structure of PUTA, α-T is considered to significantly influence the physical properties of the cell membrane.
To date, researchers' attention is focused on IP3, as minor components of the cell membranes, which play both a structural and a signaling role. Disorders of IP3metabolism in such pathologies as cancer, cardiovascular diseases, and the immune system dysfunctions, where the acoustic stress is of importance, are the red-ox and the IP3 metabolism imbalance result [36]. IP3 are the precursors of several secondary messengers of various intracellular signaling pathways.
The study of quantitative shifts in the fraction of IP3 of brain mitochondria under the conditions of acoustic stress revealed a decrease in the content of IP3 in the 2nd group compared to other experimental groups, after 7, 30 and 60 days of noise exposure.
Disorders of the metabolism of IP3, associated with the activation of free radical processes have been described in some diseases [37]. The study of quantitative changes in the fraction of IP3 of brain mitochondria under the conditions of chronic acoustic stress revealed a decrease in the content of IP3. As a result, the development of disorders in phosphorylation / dephosphorylation of the inositol ring, responsible for the implementation of regulatory mechanisms of the functional activity of membrane surface proteins and signaling complexes occur [37]. IP3 is also involved in such cellular processes, as cell growth, differentiation and survival, and the signaling regulation. Based on the results of our research, we can state that the impact of noise disrupts the above-mentioned processes leading to pathological events. However, intraperitoneal administration of beditin and mesesdin during exposure to noise has a regulatory effect on the content of IP3 after 7, 30 and 60 days of noise action. Adrenergic alpha-2 receptor antagonists exhibit the antioxidant properties and thereby prevents the lipid peroxidation intensification by maintaining the level of α-tocopherol in blood plasma and EM within physiological ranges when exposed to noise. Notably, mesedin did not cause significant changes in the studied parameters in relation to the control group, implying its higher efficacy․
Results of our previous investigations have shown that chronic noise impact increased carbonylation of FG and EM proteins [38] which also are known markers for oxidative stress, mediating redox signaling processes and development of pathology.
Considering the given study results of the α2 adrenoblockers influence on the above-mentioned processes, we can conclude that mesedin and beditin possess significant regulating properties judging by the MDA level dramatically decrease. In the given study, where mesedin was of a special significance in this regard, this effect might be probably mediated by decrease intensiveness of ROS formation and, as a result, the MDA level reduction.
Adrenaline and noradrenaline catecholamines’ effects, namely their radical scavenging activity, can be efficient for reducing oxidative stress though a loss of their activity was also mentioned [8]. Consequently, regarding oxidative stress they can be both protectors and molecular targets. It should be also noticed, under the proper conditions both catecholamines can be regenerated to their original form so their functions can be restored [39]. So, according to our previous data, one of the main advantages of α2-adrenoblocker action is its regulatory effect on lipoprotein metabolism [38]. Environmental noise has its stress-realizing effects through the direct connections to the neural mechanisms via the autonomic nervous system [40], and different mediated connections to the cerebral centers responsible for the principal physiological and behavioral effects of organism [41]. It is well-known, that the major physiological effect of α2-adrenoceptors is to block the presynaptic feedback of neurotransmitter release from noradrenergic terminals [42].
Exposure of laboratory animals to noise induced abnormal behavior, suppressed exploratory attempts and impaired memory, but some forms of chronic stress could also produce depressive-like symptoms, like anxiety [38]. The HIP is an important structure of the CNS involved in the cognitive processes’ realization, so in the pathogenesis of mood and anxiety disorders through its dorsoventral axis [43]. Recent data of some studies evident that manipulation of the vHIP itself can directly impact anxiety-related behavior [44].
The CNS peculiarities include high sensitivity to LPO due to high oxygen supply and rich content of polyunsaturated fatty acid. According to Marchasson et al., in Alzheimer's disease the MDA levels found higher in the patients’ plasma [26]. The fact, that the hippocampus is affected by noise, is well documented [15,17]. Many pathological processes, such as post-traumatic stress disorders involve HIP as the primary damage site. Changes in the neurotransmitters contents in the brain are associated with degenerative disease of CNS, brain injury and cognitive disorders [45].
For new environment accommodation in Y-maze the rats generally prefer to enter a new arm of the maze more often rather than returning one that was previously visited. The Y-maze test is a specific behavioral test for the memory and the animal’s behavior alternation assessment. The Y-maze test’s results presented in this research confirmed the harmful impact of chronic noise exposure on the animals’ spatial memory. By counting alternations sequences it was shown many incorrect alternations in the noise group. Correct alternations were BAC, CBA or ACB, etc., but in the noise group there was predominant incorrect alternations. Moreover, there was also noticed a high-level immobility in the noise group animals resulting to less distance travelled during alternation sequences, hence, the less number of entries to the different arms. This phenomenon can be explained by a deteriorating effect of noise on the organism leading to a memory weakness, and as a result, to wrong alternations.
Evidentially, the noise-induced stress led to a spatial memory deficit, which in turn brought to the orientation impairment. Observing this parameter change we recorded the exact opposite pattern in the mesedin and beditin rats’ groups. These α2-adrenobloskers decreased noise-induced stress and thus, restored anxiety-induced spatial memory.
With the OFT study our previously results had shown increased anxiety level induced by noise [39]. The increased levels of anxiety were accompanied by the immobility and disturbance orientation of rats. So, the noise-associated psycho-emotional stress is capable to mitigate anxiety-related behavior by driving a release of norepinephrine in the neuronal system of organism. Results of our study demonstrated the behavioral changes in the Y-maze tests after the α2-adrenoblockers injection, consisting in ceasing of the stress-induced immobility of rats after 60 days of chronic noise action. The anxiolytic action of α2-adrenoblockers in rats administered mesedin and beditin was expressed by reduced anxiety and increased total locomotor function.