Nucleic Acids as Novel Therapeutic Modalities to Address Multiple Sclerosis Onset and Progression.

The issue of treating Multiple Sclerosis (MS) begins with disease-modifying treatments (DMTs) which may cause lymphopenia, dyspnea, and many other adverse effects. Consequently, further identification and evaluation of alternative treatments are crucial to monitoring their long-term outcomes and hopefully, moving toward personalized approaches that can be translated into clinical treatments. In this article, we focused on the novel therapeutic modalities that alter the interaction between the cellular constituents contributing to MS onset and progression. Furthermore, the studies that have been performed to evaluate and optimize drugs' efficacy, and particularly, to show their limitations and strengths are also presented. The preclinical trials of novel approaches for multiple sclerosis treatment provide promising prospects to cure the disease with pinpoint precision. Considering the fact that not a single treatment could be effective enough to cover all aspects of MS treatment, additional researches and therapies need to be developed in the future. Since the pathophysiology of MS resembles a jigsaw puzzle, researchers need to put a host of pieces together to create a promising window towards MS treatment. Thus, a combination therapy encompassing all these modules is highly likely to succeed in dealing with the disease. The use of different therapeutic approaches to re-induce self-tolerance in autoreactive cells contributing to MS pathogenesis is presented. A Combination therapy using these tools may help to deal with the clinical disabilities and symptoms of the disease in the future.

Deep Brain Stimulation of the Lateral Hypothalamus Facilitates Extinction and Prevents Reinstatement of Morphine Place Preference in Rats.

OBJECTIVES: We have previously shown that high-frequency (HF) deep brain stimulation (DBS) of the lateral hypothalamus (LH) during the acquisition phase of morphine-induced conditioned place preference (CPP) abolished the development of morphine reward. In the present study, we investigated the effect of DBS in the LH during the extinction phase of morphine CPP. MATERIALS AND METHODS: Rats were implanted with electrodes in the LH and went through conditioning trials for morphine CPP (40 min each, for three days), followed by extinction trials (20 min, for nine days). DBS-like stimulation (square pulses at 13 or 130 Hz, 200 µA, 100 µsec) was applied during the extinction trials. RESULTS: Rats that received HF-DBS (130 Hz) accomplished extinction of morphine place preference by day 5 of the phase, whereas those in sham-stimulation or low-frequency-DBS (LF-DBS, 13 Hz) groups reached the criterion for extinction at day 8. One day later, rats received a priming injection of morphine (2 mg/kg) to reinstate the extinguished preference. While rats in the sham-DBS and LF-DBS relapsed into the state of preferring morphine-associated context, those in the HF-DBS group did not show such preference. Rats were then proceeded into an additional phase of extinction training (20 min, once daily, three to five days) with DBS, followed by restraint stress-induced reinstatement test. Again, sham-DBS and LF-DBS had no effect on relapse to the morphine place preferring state, but HF-DBS completely prevented the relapse. CONCLUSION: HF-DBS facilitated extinction of morphine place preference and disrupted drug priming- and stress-induced renewal of morphine place preference.

Electrophysiological Comparison of Definitive Pro-opiomelanocortin Neurons in the Arcuate Nucleus and the Retrochiasmatic Area of Male and Female Mice.

Pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) are considered a major site of leptin action. Due to increasing evidence that POMC neurons are highly heterogeneous and indications that the conventional molecular tools to study their functions have important limitations, a reassessment of leptin's effects on definitive POMC neurons is needed. POMC neurons are also expressed in the retrochiasmatic area (RCA), where their function is poorly understood. Furthermore, the response of POMC neurons to leptin in females is largely unknown. Therefore, the present study aimed to determine the differences in leptin responsiveness of POMC neurons in the ARC and the RCA using a mouse model allowing adult-inducible fluorescent labeling. We performed whole-cell patch clamp electrophysiology on 154 POMC neurons from male and female mice. We confirmed and extended the model by which leptin depolarizes POMC neurons, in both the ARC and the RCA. Furthermore, we characterized the electrophysiological properties of an underappreciated subpopulation representing ∼10% of hypothalamic POMC neurons that are inhibited by leptin. We also provide evidence that sex does not appear to be a major determinant of basal properties and leptin responsiveness of POMC neurons, but that females are overall less responsive to leptin compared to males.

Immunomodulatory Potential of Human Mesenchymal Stem Cells and their Exosomes on Multiple Sclerosis.

Purpose: Promising advances have been made in mesenchymal stem cell transplantation to reinducethe immune tolerance in neuroinflammatory animal models and multiple sclerosis (MS)patients. The available evidence demonstrated that immunomodulatory effects of mesenchymalstem cell are particularly exerted through releasing exosomes to their environment. Wetherefore, aimed to comparatively assess the potential effect of mesenchymal stem cells andmesenchymal stem cells-derived exosomes on proliferation and function of the CD4+CD25- conventional T cells, isolated from relapsing-remitting MS patients. Methods: Mesenchymal stem cells were isolated from human umbilical cord tissues and usedfor exosome isolation via ultracentrifugation. Both mesenchymal stem cells and mesenchymalstem cells-derived exosomes were evaluated for their anti-inflammatory effects againstthe proliferation of T cells isolated from two groups of individuals in vitro, MS patients andhealthy subjects. Cytokine production of conventional T cells (interferon-γ, interleukin-10, andinterleukin-17) was also assessed, using flow cytometry for the patients and healthy individuals. Results: Here, evidence shows that MSCs and MSC-derived exosomes dampen proliferationand percentage of conventional T cells that produce IFN-γ (healthy control: P < 0.001) andinterleukin-17 (healthy control: P <0.001, MS patients: P < 0.001), with a significant increaseof IL-10 producing cells in the patients and healthy individuals. Surprisingly, MSC-derivedexosomes demonstrated higher immune-modulating properties on conventional T cellsresponses, compared to mesenchymal stem cells (MSCs). Conclusion: The current study, provides a novel approach of exocytosis on autoimmune therapy.In particular, Mesenchymal stem cell -derived exosomes, which are cell-derived biologics,could be considered as an alternative for Mesenchymal stem cells in treating MS.