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.

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.