Abstract
Neurochemical imbalance is a contributing factor to neurological symptoms in multiple sclerosis (MS). The matured myelin sheath is crucial for substance transportation within the extracellular space (ECS) and for maintaining local homeostasis. Therefore, we hypothesize that disturbed ECS transportation following demyelinating lesions might lead to neurochemical imbalance in MS. In the current study, a lysophosphatidylcholine-induced unilateral MS model was used to investigate spatial neurochemical alterations. The results demonstrated that 168 substances were altered around the demyelination site in the ipsilateral hemisphere, compared to the contralateral hemisphere, with significant enrichment in the purine and arginine-proline metabolic pathways. Notably, dopamine was unexpectedly detected in the demyelinated region and the adjacent thalamus. Tracer-based MRI further revealed that the tracer injected into the striatum abnormally refluxed to the thalamus, with the area of reflux consistent with the altered dopamine distribution. The interstitial fluid drained extensively but was confined to the unilateral hemisphere, which may explain the observed widespread changes in other neuroactive substances. Importantly, after the restoration of ECS integrity, both interstitial fluid drainage and neurochemical imbalance, including dopamine, were normalized, supporting the potential link between ECS dysfunction and neurochemical imbalance. These observations highlight the crucial role of ECS transport in maintaining neurochemical homeostasis in the brain, providing new insights into the mechanisms that may underline the neuropsychiatric symptoms of MS.