Brain cells normally respond adaptively to oxidative stress or bioenergetic challenges, resulting from ongoing activity in neuronal circuits. During aging and in neurodegenerative disorders, these mechanisms are compromised. In fact, neurons show unique age-related changes in functions and metabolism, resulting in greater susceptibility to insults and disease. Aging affects the nervous system as well as other organs. More precisely, as the nervous system ages, neuron metabolism may change, inducing glucose hypometabolism, impaired transport of critical substrates underlying metabolism, alterations in calcium signaling, and mitochondrial dysfunction. Moreover, in neuronal aging, an accumulation of impaired and aggregated proteins in the cytoplasm and in mitochondria is observed, as the result of oxidative stress: reduced antioxidant defenses and/or increase of reactive oxygen species (ROS). These changes lead to greater vulnerability of neurons in various regions of the brain and increased susceptibility to several diseases. Specifically, the first part of the review article will focus on the major neuronal cells’ rearrangements during aging in response to changes in metabolism and oxidative stress, while the second part will cover the neurodegenerative disease areas in detail.

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Stroke remains a significant unmet clinical need with limited therapeutic options. The peculiar feature of ischemic stroke is the interruption in brain circulation, resulting in a cascade of detrimental cerebrovasculature alterations. Treatment strategies designed to maintain potency of the cerebrovasculature may protect against stroke. The present study assessed the effects of short bouts of exercise prior to stroke induction and characterized cerebral blood flow and motor functions in vivo. Adult Sprague-Dawley rats were exposed to a single short bout of exercise (30-min or 60-min forced running wheel) then subjected to transient middle cerebral artery occlusion (MCAO). Non-exercise stroke rats served as controls while nonstroke rats represented shams. Cerebral blood flow (CBF) was evaluated by laser Doppler at baseline (prior to MCAO), during MCAO, and during reperfusion. Behavioral tests using the elevated body swing test was conducted at baseline, day 0 (day of stroke), and at days 1 and 3 after stroke. Animals that received exercise displayed typical alterations in CBF after stroke, but exhibited improved motor performance compared to non-exercise rats. Exercised stroke rats showed a reduction in infarct size and an increased number of surviving cells in the peri-infarct area, with a trend towards prolonged duration of the exercise. Immunofluorescence staining and Western blot analysis of the peri-infarct area revealed increased levels of endothelial markers/angiogenesis markers, VEGF, VEGFR-2, and Ang-2, and endothelial progenitor cell marker CD34+ in exercise groups compared with the controls. These results demonstrated that prophylactic exercise affords neuroprotection possibly by improving cerebrovascular potency.

The mechanotransduction is the process by which cells sense mechanical stimuli such as elasticity, viscosity, and nanotopography of extracellular matrix and translate them into biochemical signals. The mechanotransduction regulates several aspects of the cell behavior, including migration, proliferation, and differentiation in a time-dependent manner. Several reports have indicated that cell behavior and fate are not transmitted by a single signal, but rather by an intricate network of many signals operating on different length and timescales that determine cell fate. Since cell biology and biomaterial technology are fundamentals in cell-based regenerative therapies, comprehending the interaction between cells and biomaterials may allow the design of new biomaterials for clinical therapeutic applications in tissue regeneration. In this work, we present the most relevant mechanism by which the biomechanical properties of extracellular matrix (ECM) influence cell reprogramming, with particular attention on the new technologies and materials engineering, in which are taken into account not only the biochemical and biophysical signals patterns but also the factor time.

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Neurodegenerative diseases are debilitating and currently incurable conditions causing severe cognitive and motor impairments, defined by the progressive deterioration of neuronal structure and function, eventually causing neuronal loss. Understand the molecular and cellular mechanisms underlying these disorders are essential to develop therapeutic approaches. MicroRNAs (miRNAs) are short non-coding RNAs implicated in gene expression regulation at the post-transcriptional level. Moreover, miRNAs are crucial for different processes, including cell growth, signal transmission, apoptosis, cancer and aging-related neurodegenerative diseases. Altered miRNAs levels have been associated with the formation of reactive oxygen species (ROS) and mitochondrial dysfunction. Mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases. The crosstalk existing among oxidative stress, mitochondrial dysfunction and miRNAs dysregulation plays a pivotal role in the onset and progression of neurodegenerative diseases. Based on this evidence, in this review, with a focus on miRNAs and their role in mitochondrial dysfunction in aging-related neurodegenerative diseases, with a focus on their potential as diagnostic biomarkers and therapeutic targets.

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of neuropathic pain that represents a frequent and serious consequence of chemotherapy agents. Over the last years, significant progress has been achieved in elucidating the underlying pathogenesis of CIPN. The interference of taxanes with microtubule has been proposed as a mechanism that leads to altered axonal transport and to permanent neurological damages. The inflammatory process activated by chemotherapeutic agents has been considered as a potential trigger of nociceptive process in CIPN.In this study we investigated the effect of reparixin, an inhibitor of CXCR1/CXCR2, in suppressing the development of paclitaxel-induced nociception in rats. Moreover, reparixin activity in reversing the neurotoxic effects induced by paclitaxel or GRO/KC in F11 cells was also analyzed.Reparixin administered by continuous infusion ameliorated paclitaxel-induced mechanical and cold allodynia in rats. In F11 cells, reparixin was able to inhibit the increase of acetyladed α-tubulin induced both by paclitaxel and GRO/KC. The subsequent experiments were performed in order to dissect the signal transduction pathways under GRO/KC control, eventually modulated by paclitaxel and/or reparixin. To this aim we found that reparixin significantly counteracted p-FAK, p-JAK2/p-STAT3, and PI3K-p-cortactin activation induced either by paclitaxel or GRO/KC.Overall the present results have identified IL-8/CXCR1/2 pathway as a mechanism involved in paclitaxel-induced peripheral neuropathy. In particular, the obtained data suggest that the inhibition of CXCR1/2 combined with standard taxane therapy, in addition to potentiating the taxane anti-tumor activity can reduce chemotherapy-induced neurotoxicity, thus giving some insight for the development of novel treatments.

Problem statement: Chemotherapy-induced peripheral neuropathy (CIPN) is a widespread and potentially disabling side effect of various anticancer drugs. In spite of the intensive research focused on obtaining therapies capable to treat or prevent CIPN, the medical demand remains very high. Microtubule-stabilizing agents, among which taxanes, are effective chemotherapeutic agents for the therapy of several oncologic diseases. The inflammatory process activated by chemotherapeutic agents has been interpreted as a potential trigger of the nociceptive process in CIPN. The chemotherapy-driven release of proinflammatory and chemokines has been recognized as one of the principal mechanisms controlling the establishment of CIPN. Several reports have indicated that probiotics are capable to regulate the balance of anti-inflammatory and pro-inflammatory cytokines. Accordingly, it has been suggested that some probiotic formulations, may have an effective role in the management of inflammatory pain symptoms. Experimental approaches used: we tested the hypothesis that paclitaxel-induced neuropathic pain can be counteracted by the probiotic DSF by using an in vitro model of sensitive neuron, the F11 cells. On this model, the biomolecular pathways involved in chemotherapy induced peripheral neuropathy depending on inflammatory cytokines were investigated by Real-time PCR, Western blotting and confocal microscopy. General conclusions: the results obtained, i.e. the increase of acetylated tubulin, the increase of the active forms of proteins involved in the establishment of neuropathic pain, point towards the use of this probiotic formulation as a possible adjuvant agent for counteracting CINP symptoms.