High Levels of Thyrotropin-Releasing Hormone Precursor Peptide Immunoreactivity and Binding Substance Occur in Human Cerebrospinal Fluid

Abstract

A thyrotropin-releasing hormone (TRH) precursor peptide, pGlu-His-Pro-Gly (TRH-Gly) and related peptides were measured in human cerebrospinal fluid (CSF) with a TRH-Gly radioimmunoassay and the levels of immunoreactivity (IR) were found to be 136- to 352-fold higher than the corresponding levels of TRH-IR. TRH-IR levels in CSF are elevated during the active phase of multiple sclerosis (MS). We have used this TRH-Gly RIA to determine whether this TRH precursor peptide is also elevated in CSF from MS and Alzheimer’s (ALZ) disease patients in comparison with the corresponding levels in non-central nervous system disease (control) patients. A highly significant increase in TRH-Gly-IR was observed in MS and ALZ CSF samples compared to control CSF. Cation exchange and exclusion chromatography of extracts of mixtures of CSF and synthetic TRH-Gly revealed two peaks of TRH-Gly-IR. One cochromatographed with synthetic TRH-Gly and the other was attributable to the formation of a complex between TRH-Gly and a binding substance originating in CSF. Corresponding studies with extracts of mixtures of CSF and synthetic TRH revealed no evidence for TRH binding with any component of CSF. Reverse-phase high-pressure liquid chromatography of pooled extracts of normal CSF revealed that about a third of the total TRH-Gly-IR coeluted with synthetic TRH-Gly. The half-time for in vitro metabolism of synthetic TRH-Gly in fresh CSF was 5 times longer than for synthetic TRH at 37 °C. This greater stability of the TRH-Gly-CSF binding substance complex may explain the higher levels of TRH-Gly-IR in CSF compared to TRH despite the much lower levels of TRH-Gly-IR in brain tissues compared to TRH-IR.

A Heuristic Model of Mental Depression Derived from Basic and Applied Research on Thyrotropin-Releasing Hormone

“…One extraordinary aspect of all of these clinical observations with TRH has been the rapidity of the antidepressant (AD) effects, within minutes or hours, as opposed to the usual days or weeks that are required for conventional AD drugs or ECT. The suggestion that the AD effect of intrathecal TRH is more robust than intravenous TRH is consistent with published data (7) showing that the in vitro half-time of TRH in CSF is 22 minutes versus 13 minutes in serum.…”

Electroconvulsive Seizures Increase Levels of PS4, the TRH-Enhancing Peptide [Prepro-TRH(160–169)], in Rat Brain

“…Intrathecal infusion of TRH has been reported to provide rapid reversal of symptoms of unipolar depression [16], suggest ing that a decreased expression of prepro-TRH in humans may be causally linked to this serious and widespread dis order [17,18] and also implicating TRH in the mecha nisms of the antidepressant effects of electroconvulsive therapy. TRH, however, like PS4, has a very short half time of disappearance in human serum and cerebrospinal fluid [ 19] which might limit its potential utility as a thera peutic agent.…”