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Multiple sclerosis (MS) is a progressive neurological disease of the central nervous system (CNS) and its pathogenesis has been associated with auto-immune mechanisms underlying the inflammatory demyelination of neurons. Myelin is the sheathed coating of neurons which provides multifaceted functions like neuroprotection and enhances synaptic transmission throughout brain regions. Therefore, the pathological demyelination of neurons results in distorted, slow or even the absence of neuronal communication. This consequently leads to the onset of many symptoms that characterise MS. Symptoms include mobility complications, muscle fatigue, spasms, involuntary eye movement, double vision and temporary blindness in one eye (optic neuritis).
Although the exact underlying cause of the condition remains unknown, research has found links between the onset of MS and inflammation. Microglia are the main inflammatory cells of the CNS and can detect neural lesions and demyelination. Neuronal regions and white matter of the CNS are protected from the actions of the peripheral immune system due to the blood-brain barrier. Despite this anatomical division, the infiltration of T-cells into the CNS, due to signalled recruitment from microglia, can occur. This activation and migration of immune cells causes the release of inflammatory mediators such as cytokines, as well as further migration of other immune cells like macrophages and B-lymphocytes from the peripheral immune system. Antibodies cause tissue destruction and the release of intermediate products from macrophages elicit detrimental oxidative stress. Such products include nitrogen and reactive oxygen species, found to be linked to hypoxia through impaired mitochondrial functioning. Increased inflammation of the brain ultimately can result in extensive demyelination of white matter, axonal degeneration, preventative axonal regeneration and neuronal cell death. It is yet to be determined whether the process of demyelination precedes or follows inflammation and neurodegeneration.
It has been found that MS is the most common neurological condition that young adults suffer from in the Western countries (Lassman et al). About 2,500,000 cases of MS have been reported globally, and prevalence rates in the England alone is around 164 per 100,000. Incidence rates tend to highlight that countries farther from the equator (both at a Northern or Southern distance) such as Scotland have higher MS rates. Geographical discrepancies in the epidemiology of MS imply that perhaps there are genetic factors as well as environmental effects that contribute to the susceptibility of tissue damage across individuals. Environmental factors include smoking, suggested to adversely hinder disease outcomes.
There is no cure for MS. Thus, treatments aim to prevent symptomatic relapse or further progression of the condition. Variance in symptom severity has determined the difference in treatment options prescribed to individual MS sufferers. Corticosteroid treatment, such as oral methylprednisolone, is prescribed for five days in the early presence of mild relapses. New lesions (active MS), indicated through MRI scans, tend to be treated with beta interferons. These drugs are used to reduce inflammation within the CNS.
However, draw-backs of steroid treatment for treating relapse in MS include short-term side effects like insomnia, altered mood, chest-pain and palpitations. Long-term treatment can cause weight gain and osteoporosis, consequently leading to further health implications and reduced quality of life.
Current drugs are being developed to tackle the symptoms that underlie different types of MS. An example includes Laquinimod. Research into this tablet found that it can possibly alter the activity of immune cells and therefore prevent their infiltration across the blood-brain barrier. This information subsequently implied that Laquinimod can possibly reduce neuroinflammation in the white matter as well as protect cells in the brain.
Despite these promising findings, in 2014 Laquinmod was declined at trial phase 3 stage to treat relapsing MS. Further investigations are currently being undertaken in another phase 3 trial and results of Laquinmod on relapsing MS is expected in 2019. However, the once daily tablet is now also being considered to treat primary progressive MS symptoms and currently being developed within a phase 2 trial. The effectiveness of this drug treatment shall be assessed by observing MRI scans to detect changes in brain volume and the occurrence of new neuronal lesions after administration. Low-dosage introduction of the tablet was well tolerated in trial subjects.
Moreover, investigations exploring antihistamine drug mechanisms have discovered that these compounds can also significantly influence immune response. It has been found that Clemastine fumarate, an active constituent of many antihistamine drugs, can enter the central nervous system and can use drowsiness. The side effects of drowsiness and dizziness are common, particularly when antihistamine drugs are prescribed for conditions such as hay fever. Therefore, Clemastine fumarate’s transport capability, across the blood-brain barrier, highlighted promising potential of the drug in treating neurological conditions like MS.
Phase 1 trials conducted in 2010 found that subjects who had their immune cells injected with the Clemastine showed reduction in cellular activity and can promote myelin repair after pathological demyelination. It is currently in phase 2 trial testing for relapsing MS due to its immunosuppressive competence and potential therapeautic effects in other conditions. However, the compound is yet to be administered in MS sufferers. Therefore, the true extent of possible side effects for MS patients remains unknown and requires further investigation.
Furthermore, prevalent aspects of the condition such as neuronal cell death and axonal degeneration, are also being considered in drug discovery. Ibudilast (MN-166) is undergoing development for progressive MS. This drug is a phosphodiesterase inhibitor and its proposed mode of action is to reduce inflammatory activity in order to prevent neural cell deficiency. It can conduct this function by supressing pro-inflammatory cytokines. Phase 2 trial investigations suggested that though Ibudilast did not impact distinct lesion occurrence and subsequent relapsing MS, neuroprotective capabilities were evident through the reduced progression of MS in subjects.
As previously mentioned, the release of reactive oxygen species, from migrated immune cells, in the CNS can pathologically exacerbate MS symptoms. Research conducted to tackle this biological target has found that common antioxidants like Lipoic acid (LA) can reduce inflammation. Damage to the myelin sheath is thought to proceed the autoimmune attacking of myelin by T-cells, resulting in heightened inflammation. LA provides a significant proposition in treating symptoms of MS. It can potentially modulate the immune response as well as yield anti-inflammatory effects in order to provide neuroprotection.
A pilot study published in the Multiple Sclerosis journal (2005) found that oral LA administration reduced the levels of T-cell migration into the CNS in 37 sufferers. LA was well tolerated and absorbed. This further implies the effectiveness of LA as prime MS treatment. Following this, the oral drug has undergone another pilot study, a phase 1 trial completed in 2016 and is currently in phase 2 trial status. The phase 2 trial has begun in 2017 and will be longitudinal in order to assess mobility of sufferers after two years.
However, the use of LA in other conditions has shown side effects such as muscle cramps and headaches. The risk of muscle cramps in particular may deter MS patients from using this medication due to the belief that this symptom can aggravate others of their disease such as motility. Furthermore, the high-dosage of orally administered LA in the trial (1,200mg) highlights the drug’s lower potency. This can also cause issues with patient compliance as it may require treatment to be administered through multiple oral tablets a day, rather than just one.
Moreover, LA still does have significant beneficial potential over existing treatments. It was found in 2016 that the drug can also reduce brain atrophy, implying a neuroprotective role. Advantageous potential of this drug intervention is that it is dual-tackling. This includes modulation of immune cell activity but also potential rehabilitation of anatomical damage in MS. This suggests preventative measures for onset as well as blocking further degeneration. Therefore, this evidence illustrates that LA is the best possible treatment for this neurological condition. This is due to the multiple action that LA can exhibit, in comparison to other compounds that only target individual aspects of the condition.
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