Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment

From: <a href="https://www.ncbi.nlm.nih.gov/pubmed/19557103/">Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related condi... - PubMed - NCBI</a>

Certain neurological fatigue-related conditions such as MS, ALS, PD, and CFS often present with fatigue and other neuropsychiatric symptoms including memory and concentration loss, emotional lability, and confusion. Whether these conditions refl ect related neuroinfl ammatory and neurodegenerative molecular pathology is speculative. However multisystem involvement including cerebrospinal effects of these conditions could be explained in part through PACAP and VIP compromise. In particular, cerebrovascular and spinovascular effects at the ultramicroscopic level involving BBB/BSB may contribute to these disorders. Compromise of PACAP and VIP or their receptors may have a role and should be the subject of further research. Evidence for compromise of these VN receptors at different levels including VN receptor mRNA, protein transcription, cellular migration and traffi cking, cell membrane localization and possible antibody or T cell targeting may provide an explanation for some of the etiology of these disorders. Alternatively, antagonist short-form variants of VNs themselves may exist through faulty protein manufacture and produce a similar clinical picture. If PACAP and VIP do indeed fail, through autoimmunity of their receptors, MHCII molecules usually expressed at low levels in BBB, eg, in microglia/pericytes, and normally kept in check by PACAP and VIP, may be at risk of becoming overexpressed. This may be the initiating event for BBB/ BSB breakdown and subsequent neuroinfl ammation and/or neurodegeneration in MS, PD, and ALS. Why CFS does not proceed to result in further demonstrable neurodegenerative pathology is not clear under this model although confi rmatory studies have not been done to date. The possibility that PACAP/VIP failure also leads to Treg impairment, possibly through impaired Foxp3 expression, is also yet to be investigated. Treg impairment has been described in MS patients suggesting possible PACAP/VIP failure.

PDEs metabolize cAMP and serve to regulate cAMP levels. PACAP/VIP compromise will result in impaired AC activation and hence impaired cAMP production. Noting the cAMP-protecting effects of PDEIs there is evidence to suggest PDEIs may have a role in treatment for certain neuropsychiatric fatigue-related conditions.