Tuesday, 2 February 2016

Fingolimod making memories

Efstathopoulos P, Kourgiantaki A, Karali K, Sidiropoulou K, Margioris AN, Gravanis A, Charalampopoulos I. Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory. Transl Psychiatry. 2015 Nov 24;5:e685. doi: 10.1038/tp.2015.179.

Fingolimod (FTY720) was the first per os administered disease-modifying agent approved for the treatment of relapsing-remittingmultiple sclerosis. It is thought that fingolimod modulates the immune response by activating sphingosine-1 phosphate receptor type 1 (S1P1) on lymphocytes following its in vivo phosphorylation. In addition to its immune-related effects, there is evidence that fingolimod exerts several other effects in the central nervous system, including regulation of the proliferation, survival and differentiation of various cell types and their precursors. In the present study, we have investigated the effect of fingolimod on the production of new neurons in the adult mouse hippocampus and the association of this effect with the ability for pattern separation, an established adult neurogenesis-dependent memory function. Immunofluorescence analysis after chronic administration of a physiologic dose of fingolimod (0.3 mg kg(-1)) revealed a significant increase in both the proliferation and the survival of neural progenitors in the area of dentate gyrus of hippocampus, compared with control animals. These effects were replicated in vitro, in cultures of murine hippocampal neural stem/precursor cells that express S1P1 receptor, suggesting cell-autonomous actions. The effects of fingolimod on neurogenesis were correlated to enhanced ability for context discrimination after fear conditioning. Since impairment of adult hippocampal neurogenesis and memory is a common feature of many neuropsychiatric conditions, fingolimod treatment may be beneficial in therapeutic armamentarium of these disorders

Contextual fear memory is that you put the animals in a say black box and you electric shock them so that the animals associate the black box with the shock and so when they see the box they freeze because they are waiting for the shock to come, which doesn't arrive. In the past we have shown that motor-co-ordination on the rotorod (accelerating wheel) that is lost due to inflammatory attack can improve if fingolimod was administered early enough. This was not associated with remyelination as far as we could tell. Was this improvement due to the production of new sysnapses that allowed for a functional recovery? In this study they look in a part of the hippocampus, the dentate gyrus and they see that neural stem cells are producced. In addition the subventricular zone is another area for neurrogenesis (production of nerves), So fingo appears to promote neurogenesis.  Is this relevant to all brain regions or just areas of memory?

However we shown that if the treatment fingo was started too late then that progressive deterioration occurred in the beasties and movement disability progressed. This was found in primary progressive MS. Isthis the end of fingolimod as treatment for progressive MS. Is this a blot on the fututre of S1P1 modulators? or is it just fingolimod. It is hard to see why Siponimod will not go the same way in secondary progressive MS as the targets are the same and progressive PPMS and SPMS are the same. We wait to see.

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