Role of neuroinflammation in the symptoms associated to neuropathic pain: targeting microglia with innovative treatments

The immune system in mammals contains a wide array of cells which serves to maintain normal physiologic conditions and promote the repairing processes of damaged tissues. Many of these activities are mediated by soluble factors, such as chemokines and cytokines, which are released from immune cells and bind to specific receptors or interact with other cellular targets, resulting in the activation of selected genes. This cross talk between different cell types maintains the homoeostatic balance of the immune system. Microglia cells, located in the brain and spinal cord, represent the immune cells of the central nervous system (CNS) and, along with astrocytes, constitute the first line of defense in the CNS. Several studies developed over the years show that a lesion of peripheral nerves can lead to the variation of plasticity in central synapses at structural and functional level. Specifically, these alterations lead to an imbalance between excitatory and inhibitory synapses in the dorsal horns of the spinal cord where we find the pain pathways, which could be the cause of the phenomenon of hypersensitivity at the base of the pathophysiological process. The origin of this imbalance is still not fully clarified, but with increasing certainty it has emerged how the activation of microglia cells present at the spinal level could play a fundamental role. Neuropathic pain (NP) is the most difficult to treat type of pain; the patient hardly achieves a complete analgesic effect, but only obtains a reduction in symptoms. Therefore, therapy is often unsatisfactory due to both the poor efficacy and side effects of the drugs used. The purpose of this thesis is precisely to find innovative therapies that target factors involved in microglial activation and its shift into pro-inflammatory microglia. In NP, microglia represent a key modulator of the various processes that characterize this chronic and disabling disease, which can be summarized as: neuroinflammation, neurodegeneration, and demyelination. The multiple mechanisms of the innovative treatments studied in this work for reducing microglial activation produced two main effects: reduction of neuroinflammation by promoting the phenotypic shift of microglia, and counteraction of demyelination. Our findings highlight the key role of microglia in the neuronal maintenance and open a broader vision of NP therapy through an approach that can resolve the causes rather than being a simple symptomatic intervention. The targets on which we have mainly focused our attention are modulators of genetic transcription: HDAC1 and HuR, and their silencing with different therapeutical approaches, induced a slow-down of pathology. Innovation is also brought by the type of administration used, the intranasal delivery, which have an effect at the level of the CNS in a non-invasive way compared to more complex and disabling routes such as intrathecal. In fact, the use of non-invasive routes favors an increase in compliance with the patient, which also ensures a higher effectiveness of therapies and increases quality of life. Neuropathies are chronic diseases whose main symptoms are associated with pain, but which involve, given their difficulty in resolving, the onset of long-term comorbidities such as anxiety, depression, insomnia, and loss of cognitive ability. Using a marker of cellular senescence, we evaluated the possible development of microglial aging at the level of the spinal cord (central site of pain) and of the hippocampus (important site of the development of anxiety and depression). Indeed, preventing microglial senescence means reducing the possibility of having an alteration in the homeostasis of the CNS, that leads to aging and deterioration of the cognitive abilities of the person. Another aspect that has emerged rather recently is the possible connection between microglia and all kind of addictive conditions, including those produced by alcohol. Indeed, about 50% of individuals who exhibit alcohol dependence develops the so called “alcoholic neuropathy”. In the spinal cords of alcohol-dependent animals that develop neuropathy, we observed an increase in the expression of microglial markers, thus opening a new avenue in the possible involvement of microglia also in these forms of neuropathy. In conclusion, a stressful correlation between neuroinflammation, demyelination, and degeneration in central and peripheral neuropathies was observed in this thesis. Given that microglia activation is an important crossroads in the onset and regulation of these processes, this work suggest that its role should be more deeply investigated and considered as an important drug target. Indeed, restoring normal physiological conditions in the nervous environment through the modulation of specific microglial targets is an innovative approach to move towards more effective, safe, and personalized therapies.