Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus.

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.

Changes in the level of fatty acids in the brain of rats during memory acquisition.

Memory acquisition is accompanied by many cellular and molecular processes, and it is not always clear what role they play. Fatty acids (FAs) are known to be important for cognitive functions, but the details of their involvement in memory processes remain unknown. We investigated FAs in the prefrontal cortex and hippocampus of rats trained to perform a task with food reinforcement. The learning consisted of two training sessions, each of which included 10 trials. The results showed that such training altered individual FAs in the brains. The most significant changes were in the prefrontal cortex, where an increase in the level of many FAs occurred, especially after the second training session: palmitic (16:0), stearic (18:0), docosahexaenoic (22:6, n-3), arachidonic (22:4, n-6), docosapentaenoic (22:5, n-6) acids. Changes in the fatty acid level after training in rats were detected only in the left hippocampus, where the levels of palmitic, docosapentaenoic, and docosahexaenoic acids changed. The changes in the right hippocampus were not significant. In both the prefrontal cortex and the left hippocampus, 72 h after training, all FAs returned to control levels. We believe that the main role of a reversible increase in FA levels during memory acquisition is to support and protect cellular processes involved in memory acquisition. Consolidation of memory traces, which occurs mainly in the neocortex, requires protection from external influences, to which FAs makes a significant contribution. They are able to improve neuronal plasticity, enhance local blood flow, improve mitochondrial processes, and suppress pro-inflammatory signals.

Why Do Levels Of Anti-inflammatory Cytokines Increase During Memory Acquisition?

The role of anti-inflammatory cytokines in the mechanisms of learning and memory, modulation of synaptic plasticity in the mammalian brain has not received sufficient attention. These issues are discussed in this review, and among the many cytokines, attention is paid to the most studied in this respect IL-10, IL-4, IL-13 and TGF-ß. The level of anti-inflammatory cytokines in the brain tends to increase during memory acquisition, but the significance of such an increase is unclear. We hypothesize that anti-inflammatory cytokines primarily protect and optimize the functioning of neuronal circuits involved in information processing. The increased local activity of neurons during memory acquisition activates many signaling molecules, and some of them can trigger unwanted processes (including neuroinflammation), but increased levels of anti-inflammatory cytokines prevent this triggering. Each of the anti-inflammatory cytokines plays a specific role in supporting information processing. For example, the role of IL-4 and IL-13 in recruiting T cells to the meninges during training in healthy animals has been most studied. It has also been shown that TGF-ß is able to optimize late stage LTP in the hippocampus and support the consolidation of memory traces in behavioral studies. Cytokines have an effect on learning and memory through their influence on neuroplasticity, neurogenesis in the hippocampus and regulation of the neurovascular unit. Experiments have shown such an effect, and the data obtained create the prerequisites for new therapeutic approaches to the correction of cognitive impairments.

The role of anti-inflammatory cytokines in memory processing in a healthy brain.

The purpose of the work was to study the role of anti-inflammatory cytokines in memory processing in a healthy brain. Wistar rats were trained to perform a task with positive (food) reinforcement; and then the task performance was tested after intraventricular injection of IL-10 or TGF-ß1. A microinjection into the brain of either of the two cytokines did not affect the performance of the task and did not have an anti-amnesic effect when the retrieval was deteriorated with scopolamine. In addition, endogenous levels of IL-10 and TGF-ß1 were determine in the prefrontal cortex and in the hippocampus after one and two training sessions, consisting of 10 runs each. The level of IL-10 did not change after training both in the prefrontal cortex and in the hippocampus. Endogenous level of TGF-ß1 increased in the neocortex after the first training session, the second session, and recovered to the normal level three days after training. In contrast, in the hippocampus, the level of TGF-ß1 was decreased: maximally after the first training session in the right hippocampus and after the second training session in the left one. Given the role of the prefrontal cortex in memory processing, we assume that a specific increase of TGF-ß1 in the prefrontal cortex may indicate involvement in memory trace consolidation.

Deficiency of transforming growth factor-ß signaling disrupts memory processes in rats.

Cytokines, in addition to their participation in immune and inflammatory processes, play an important role in synaptic plasticity, neoneurogenesis, and cognitive functions. In our work, we aimed to clarify the role of the transforming growth factor-ß (TGF-ß), which is recognized as a multifunctional cytokine, in memory processes. Behavioral experiments were carried out in rats using step-through passive avoidance test. The results obtained showed that the learning of animals after treatment with SB431542, a selective inhibitor of TGF-ß receptors, was impaired, which indicated a significant memory deterioration. Nevertheless, the memory of rats remained at the control level when TGF-ß and SB431542 were coadministered. Thus, the role of TGF-ß in memory retrieval after the passive avoidance test was revealed: memory in rats was weakened if the TGF-ß signaling pathway was inhibited during learning. Evidently, successful consolidation of at least some types of memory requires a normal level of TGF-ß, indicating the modulation of cognitive functions by cytokines under normal physiological conditions.