Effects of Low Field Magnetic Stimulation on Brain Remyelination and Cog-nitive impairment in the Chronic Cuprizone Demyelination Mouse Model of Multiple Sclerosis

Abstract

Multiple Sclerosis (MS), a chronic inflammatory demyelinating disease of the Central Nervous System (CNS), is recognized as the leading cause of disability in young adults in Canada. The pathological features of MS include neuroinflammation, demyelination, and oligodendrocyte (OL) loss. Cognitive impairment (CI) and depression are the most common neuropsychiatric symptoms and major determinants of MS disability. Despite the broad and severe spectrum of signs and symptoms, we are still missing effective treatment methods that can be applied to treat MS. Low field magnetic stimulation (LFMS) is a novel non-invasive neuromodulation technology. A few clinical and animal studies have shown that LFMS has beneficial effects on emotional disturbances and cognitive function. Our research has shown that LFMS ameliorated cuprizone (CPZ)-induced working memory deficits and depression-like behaviours in the mice. The cur-rent study aimed to assess the effects of LFMS on cognition and remyelination in a CPZ-induced chronic demyelination model of MS. Eight-week-old female C57BL/6 mice were fed with 0.2% of CPZ (w/w) for 12 weeks (12w) to induce chronic brain demyelination. The mice resumed the regular diet and received 20-min LFMS or Sham treatment every day for five days a week. The treatments lasted for two (14w) or four weeks (16w) to study the effects of LFMS on locomotor functions, anxiety and depres-sion-like symptoms, as well as working memory using behavioural tests at the different time points (12w, 14w, and 16w). The animals were then euthanized, and the brain samples were col-lected and stored at -80°C for future experiments (Western blots and immunohistochemistry). The results showed that chronic CPZ administration led to working memory deficits and de-pression-like behaviours. The gross locomotor function and anxiety-like behaviours were not affected by CPZ. LFMS treatment significantly enhanced the expression of myelin basic pro-tein (MBP) and myelin oligodendrocyte glycoprotein (MOG). LFMS also increased the expres-sion of Glutathione S-transferase (GST-π), a mature OL marker. LFMS reduced the level of Glial Fibrillary Acidic Protein (GFAP), an activated astrocyte marker, and pro-inflammatory factor Tumor necrosis factor-alpha (TNFα). There was a significant reduction in the number of overall OL lineage cells labelled with Olig-2 (Oligodendrocyte Transcription Factor 2). A sig-nificantly enhanced expression of TGF-β (Transforming Growth Factor beta) and the receptors (TGF-β R1 and TGF-β R2) involved was reported. Our results show that LFMS enhanced cognitive function and alleviated depression-like behav-iours. LFMS facilitated the remyelination process in mice with chronic demyelination. LFMS may exert its therapeutic effects by reducing neuroinflammation and promoting OL regenera-tion through the TGF-β pathways. These results suggest that LFMS can be a promising thera-peutic method for depression and cognitive impairment in MS patients. In addition, LFMS may also facilitate remyelination through its neuroprotective and immunomodulating effects, but this remains to be shown. Further studies are warranted to understand the detailed molecular mechanisms which facilitate the remyelination processes and behavioural deficits.