PEGylation enhances the therapeutic potential for insulin-like growth factor I in central nervous system disorders.

OBJECTIVE: Due to its potent neurotrophic activity, insulin-like growth factor I (IGF-I) has been proposed many times for therapeutic application in disorders of the central nervous system (CNS). However, insufficient brain delivery to yield beneficial central without peripheral side effects have prevented clinical development in most instances. DESIGN: We recently reported the generation of a polyethylene-glycol modified IGF-I variant (PEG-IGF-I) with prolonged half-life and less acute side effects, but with fully maintained slow anabolic activity. Here we investigated if these beneficial properties result in improved brain availability of the drug, thereby reaching therapeutically relevant steady-state concentrations to elicit beneficial effects on neuronal function. RESULTS: After a single subcutaneous injection, PEG-IGF-I reached much higher steady-state levels in brain tissue and cerebrospinal fluid compared with IGF-I. Two weeks treatment with PEG-IGF-I was sufficient to modulate brain plasticity processes, as judged by changes in synaptic proteins and related animal behavior. Furthermore, chronic treatment of a mouse model of brain amyloidosis with PEG-IGF-I reverted deficits in insulin/IGF-I signaling, synaptic proteins and cognitive performance. CONCLUSIONS: Our data generate the therapeutic potential for PEG-IGF-I to treat CNS disorders by systemic drug application, and in addition scientifically support its application in disorders of synaptic function and neuronal development.

Age-related impairments in operant DMTP performance in the PS2APP mouse, a transgenic mouse model of Alzheimer's disease.

One of the earliest signs of Alzheimer's disease (AD) is loss of memory for recent events. This deficit in short term memory has been characterised in mild/moderate AD patients as a delay-dependent deficit in a delayed matching to sample (DMTS) task. PS2APP mice co-expressing hPS2mut and hAPPswe exhibit a spatial-temporal elevation in brain amyloid deposition and inflammation associated with temporal cognitive decline. The aim of the current study was to train PS2APP mice (C57BL/6JxDBA/2 mixed background) and appropriate control mice (B6D2F1 background) in a rodent delayed response task, the delayed matching to position (DMTP) task, prior to the onset of plaque formation and subsequently at 2-4 monthly intervals to investigate the effect of aging and increasing plaque load on DMTP performance. At 5 months of age (baseline) DMTP performance was equivalent with both PS2APP and control mice demonstrating a working memory curve across increasing delay intervals of 1-24s. A comparison of PS2APP and control mice across ages revealed a selective age-related, delay-dependent, impairment on choice accuracy in PS2APP mice, consistent with the cognitive decline and temporal amyloidosis previously described for this mouse model. These data are also relevant for other conditional transgenic mouse models which allow time-sensitive induction or inhibition of gene expression such that mice can be trained to perform the task prior to activation or inactivation of the gene and tested thereafter.

Effect of a thyrotrophin-releasing hormone analogue, RX77368, on AMPA-induced septal-hippocampal lesioned rats in an operant delayed non-matching to position test.

The aim of the present study was to determine the effect of a thyrotrophin-releasing hormone (TRH) analogue, RX77368, on performance of a working memory test, using a delayed non-matching to position (DNMTP) procedure, in (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced septal-hippocampal lesioned rats. Following a post-surgery recovery period, pretrained rats were tested once daily on DNMTP, 30 min post-administration of RX77368 (1.0 mg kg-1, i.p.) or saline. AMPA-induced lesions significantly reduced percent correct responses during the second week of testing. Comparison of percent correct responses between days 1 and 13 of testing showed that sham rats significantly improved DNMTP performance, whereas lesioned rats did not. RX77368 significantly reduced general locomotor activity in sham rats in activity boxes, but did not disrupt non-mnemonic measures, such as locomotion and motivation, in the DNMTP test. RX77368 increased percent correct responses in AMPA-lesioned rats on days 8-10 and 11-13. There was also a significant improvement in percent correct responses achieved between day 1 and 13 in RX77368-treated lesioned and sham rats. These results showed that: (i) septal-hippocampal lesioned rats did not improve over the testing period; and (ii) on test days when a significant impairment was present, RX77368 partially improved DNMTP performance.