M. R. Novikova

Chronic combined stress induces selective and long-lasting inflammatory response evoked by changes in corticosterone accumulation and signaling in rat hippocampus.

Hippocampus is believed to be selectively vulnerable to stress. We hypothesized that this phenomenon may be mediated by relatively high vulnerability to neuroinflammation related to impairments of local glucocorticoid metabolism and signaling. We have evaluated inflammatory responses induced by acute or chronic combined stress in the cerebral cortex and hippocampus as well as circulating and brain corticosterone (CS) levels as well as expression of corticosterone target genes. The hippocampus showed higher stress-induced expression of the proinflammatory cytokine IL-1β as compared to the cerebral cortex. A month after the termination of the chronic stress, IL-1β mRNA in the cerebral cortex reached control level, while in the hippocampus it remained significantly increased. Under chronic stress, the maladaptive inflammatory response in hippocampus was accompanied by a significant increase in local CS levels, as compared to cerebral cortex. Under acute stress, the increased CS level induced changes in CS-regulated genes expression (CRF and IGF1), while this phenomenon was not observed after chronic stress. Thus, the hippocampus appears to be more vulnerable to stress-induced inflammation as compared to the neocortex and demonstrates persistent inflammatory response induced by chronic stress. Stress-induced maladaptive inflammatory response is associated with a selective increase in hippocampal CS accumulation and changes in CS signaling.

Changes in the expression of astroglial and microglial markers in the hippocampus of rats adapted to chronic stress and the effects of panthenol

We studied the morphological changes and expression of the astroglial and microglial markers in the sensorimotor cortex and hippocampus of rats that were subjected to chronic stress. Chronic neurotization was associated with the appearance of a large number of damaged neurons in layer V of the sensorimotor cortex and the pyramidal layer of the hippocampus. These changes were considerably expressed in the CA3 field. A neurosis-like state in rats was accompanied by an increased expression of microglial markers in the hippocampus and this effect was evident even 1 month after the end of stress. The expression of the astroglial marker GFAP decreased in the CA3 hippocampal field. Treatment of animals with the pantothenic acid derivative panthenol stabilized the glial response to chronic stress; however, its effects were not long-lasting and did not prevent activation of microglia during the period after stress.

The Acute Post-Traumatic Period in Rats Is Accompanied by an Anxiety State and a Decrease in the Proportion of REM Sleep

The sequelae of craniocerebral trauma (CCT) were studied using a model based on severe (3–4 atm) lateral hydrodynamic percussion (liquid-percussive brain injury) in male Sprague–Dawley rats. With the aim of detecting the symptoms of anxiety states, the rats’ behavior was assessed in the dark-light box and the elevated plus maze test; sleep impairments were detected by recording the electrocorticogram (ECoG) before trauma and during the first week after trauma. The results provided evidence of the post-CCT development of signs of an anxiety state, accompanied by decreases in the proportion of REM sleep and decreases in the amplitude and frequency of the ECoG during this phase.

Specific Activity Features in the Forced Swim Test: Brain Neurotrophins and Development of Stress-induced Depressive-like Behavior in Rats

Selective vulnerability or resilience to mood disorders is related to individual differences or personality. In the present study forced swim test (FST) was used as a tool for division of male rats according to their immobility behavior. The animals were subjected to a chronic unpredictable mild stress (CUS). Depressive-like behavior and modifications in brain neurotrophin system of were examined after CUS exposure. The low immobile (LI) and high immobile (HI) rats demonstrated elusive differences in expression of BDNF ExVI mRNA and TrkA mRNA which was higher in the hippocampus and frontal cortex, respectively, of HI rats as compared to LI animals. Exposure to CUS resulted in development of depressive-like phenotype and increased anxiety in both subgroups; however, immobility in FST specifically decreased in the initially HI animals. In hippocampus of stressed LI rats, the contents of total BDNF mRNA decreased. In hippocampus of stressed HI rats, the content of TrkA mRNA increased whereas in frontal cortex, the content of BDNF exon I mRNA decreased in both LI and HI rats. The levels of BDNF ExIX and ExI as well TrkB mRNAs were higher in the hippocampus of HI rats as compared to LI rats. In general, the response of hippocampus to CUS was much more expressed as compared to frontal cortex. Thus, initially different stress coping strategies of rats in the FST (HI, LI) were associated with the development of similar behavioral phenotypes after chronic unpredictable stress; however, these phenotypes were associated with different alterations in neurotrophin systems of the brain.

The Effects of Cortexin on Free-Radical Oxidation and Inflammatory Processes in Rats with Normal and Accelerated Aging

We studied the geroprotective properties of Cortexin and the systems of free-radical oxidation and inflammatory processes as potential targets of this drug. The study used 12-month-old male Wistar and OXYS rats with normal and accelerated aging, respectively. After preliminary assessment of their behavior in the open-field test, the rats were divided into homogenous groups according to behavioral indices. The animals were intraperitoneally injected with Cortexin (Geropharm, Russia) at a dose of 1 mg/kg daily for 30 days. The course of treatment with Cortexin did not substantially affect the general conditions and behavioral indices of both Wistar and OXYS rats and had a moderate positive effect on cognitive functions. Cortexin corrected the state of the systems of free-radical oxidation and cytokines. Specifically, in the brains of OXYS rats, Cortexin restored the ratio of the pro- and antioxidant systems primarily in the neocortex; however, a systemic effect was also observed. A significant anti-inflammatory effect was found at the systemic level and in the brain.

Changes in the Cerebral Cortex after Dosed Craniocerebral Trauma in Rats of Different Ages

Dosed lateral fluid percussion was used to model craniocerebral trauma (CCT) of moderate to severe intensity in one- and two-year-old rats. Brain sections were stained with cresyl violet by the Nissl method and with an immunochemical reaction for glial fibrillary acidic protein (GFAP) – a marker for astrocytes. The results provide evidence that zones of direct and remote injury formed in the side ipsilateral to the blow. The direct injury zone corresponded to the area of direct contact of the column of liquid with the dura mater, while the remote injury zone was positioned lateral and caudal to the direct injury zone. Morphological detection of trauma depended on the strength of the blow and was seen in both age groups as astrocytic gliosis, with thinning of layer I of the cortex due to death of neurons. Signs of ischemic changes to neurons were probably associated with local impairment to blood supply. Brain damage in one-year-old rats was local in nature but was more diffuse in two-year-olds, while gliosis was characterized by inhomogeneity. The reproducibility and appropriateness of the model allow it to be used for investigation of the molecular genetic mechanisms of the sequelae of CCT in humans and for identifying common mechanisms in the sequelae of CCT and the pathogenesis of major diseases comorbid with CCT, particularly depression and epilepsy.

Combined treatment with pantothenic acid derivatives and memantine alleviates scopolamine-induced amnesia in rats: The involvement of the thiol redox state and coenzyme A

Free-radical-mediated processes are involved in a variety of physiological events, while oxidative stress and related redox deregulation are implicated in various pathological events. Tripeptide glutathione plays an important role in the antioxidant defense of the brain, particularly in the maintenance of the optimal redox state in neurons and glial cells. We studied the combined effects of pantothenic acid derivatives, pantothenol and calcium pantothenate, and memantine, which is a glutamate receptor antagonist that is widely used for the treatment of dementia, on amnesia induced by scopolamine in rats. Scopolamine induced amnesia in rats; however, unexpectedly, this effect was even more expressed in the memantine-pretreated animals. Memory impairments were less manifested in the rats that were pretreated with memantine in combination with panthenol or calcium pantothenate. The detrimental scopolamine effect on memory was accompanied by significant depletions of glutathione and coenzyme A in the brain. While memantine recovered the glutathione status to some extent, it nevertheless further aggravated the scopolamine influence on coenzyme A levels. An alleviation of scopolamine-induced memory impairments that was observed after combined pretreatment with memantine and panthenol or calcium pantothenate was accompanied by a normalization of coenzyme A levels, while the effects on glutathione redox did not correlate with the behavioral data.