Decreased levels of repulsive guidance molecule A in association with beneficial effects of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients

Abstract

Repeated intrathecal application of the sustained release steroid triamcinolone acetonide is beneficial in progressive multiple sclerosis patients. Its putative regenerative effect may involve regulation of the repulsive guidance molecule A synthesis. This protein inhibits axonal regeneration and functional recovery. Objectives were to demonstrate the efficacy of four triamcinolone applications every other day in association with repulsive guidance molecule A levels in cerebrospinal fluid. Clinical evaluation was performed at baseline and on each day after a triamcinolone administration in 25 progressive multiple sclerosis patients. Repulsive guidance molecule A concentrations were determined before each triamcinolone application by western blot analysis with quantification. Clinical scores for multiple sclerosis improved, and the maximum walking distance and speed ameliorated in 17 patients. Repulsive guidance molecule A levels declined in these responders. The remaining patients showed no prompt clinical benefit and no decrease of repulsive guidance molecule A concentrations. Decline of repulsive guidance molecule A may reflect regeneration and functional recovery by triamcinolone in progressive multiple sclerosis patients.

One-time intrathecal triamcinolone acetonide application alters the redox potential in cerebrospinal fluid of progressive multiple sclerosis patients: a pilot study

“…This decline generally precedes neuronal recovery. One may even hypothesize that changes of free radical metabolism may trigger the observed descent of RGMa concentrations in patients with an enhancement of MS symptoms during TCA treatment [Müller et al 2014[Müller et al , 2015. However, this hypothesis warrants further investigation in combination with repeat clinical evaluation of MS patients, and assessment of further metabolic CSF substrates that are responsible for regenerative processes according to a similar signal-transduction pathway as in the case of fibrinogen generation [Aiken et al 2011].…”

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

“…Therefore, the underlying research method is worth to be considered for a modification. As an alternative to this misconception, one may consider the stimulation of an existing repair system in the peripheral and central nervous system as a more promising research paradigm [115][116][117][118][119][120]. Therapeutic strategies, which antagonize the repulsive guidance molecule A (RGMa) pathway, are worth for further development in clinical trials.…”

“…Therefore, it is hypothesized that other syndromes than PD and AD, may also respond to this approach [118,120,123,129,130]. It may restore neuronal function in the long term as a general concept for repair and may weaken efficiency of toxin exposure [46,116,117,125,126,[131][132][133]. Well designed, clinical long term trials with RGMa antagonizing approaches are urgently needed in multiple sclerosis, PD, dementia syndromes, stroke, or spinal cord injury.…”

Repulsive Guidance Molecule‐a and Central Nervous System Diseases

“… Alter the permeability of blood-brain barrier (BBB): the damage of BBB is an important pathological feature of MS [ 42 , 43 ]. Studies have found that the level of RGMa in cerebrospinal fluid in patients with triamcinolone acetonide treatment (its pharmacological effect is mainly on improving the BBB permeability) is reduced, which suggested that RGMa may be involved in the pathology of MS by regulating BBB permeability in MS patients ( Table 1 ) [ 44 , 45 ]. …”