MRZ-99030 - A novel modulator of Aß aggregation: II - Reversal of Aß oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.

ß-amyloid1-42 (Aß1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aß oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aß aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aß1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aß species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aß oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aß1-42 interferes with the glutamatergic system and with neuronal Ca(2+) signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100-500 nM) at a 10:1 stoichiometric excess to Aß clearly reversed the synaptotoxic effects of Aß1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca(2+) levels in pyramidal neuron dendrites and spines triggered by Aß1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aß1-42. Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aß1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD.

GW406381, a novel COX-2 inhibitor, attenuates spontaneous ectopic discharge in sural nerves of rats following chronic constriction injury.

There are several lines of evidence to suggest that cyclooxygenase-2 (COX-2) plays an important role in the generation and maintenance of neuropathic pain states following peripheral nerve injury. However, COX-2 inhibitors are generally ineffective in reversing mechanical allodynia and hyperalgesia in models of neuropathic hypersensitivity. Here, we have investigated the effects of GW406381, a novel COX-2 inhibitor, on mechanical allodynia, hyperalgesia and generation of spontaneous ectopic discharge in rats following chronic constriction injury (CCI) of the sciatic nerve and compared it with rofecoxib. GW406381 (5mg/kg, 5 days of treatment) significantly reversed the CCI-induced decrease in paw withdrawal thresholds (PWTs), assessed using both von Frey hair and paw pressure tests, whereas an equi-effective dose of rofecoxib (5mg/kg, 5 days of treatment) in inflammatory pain models was ineffective. In rats treated with GW406381, the proportion of fibres showing spontaneous activity was significantly lower (15.58%) than that in the vehicle (32.67%)- and rofecoxib (39.66%)-treated rats. Ibuprofen, a non-selective COX inhibitor, at 5mg/kg, orally dosed three times a day for 5 days did not significantly affect the PWTs in CCI rats. In naïve rats, GW406381 did not significantly change the PWTs. These results illustrate that COX-2 may indeed play an important role in the maintenance of neuropathic pain following nerve injury, but that only certain COX-2 inhibitors, such as GW406381, are effective in this paradigm. Whilst the mechanisms underlying this differential effect of GW406381 are not clear, differences in drug/enzyme kinetic interactions may be a key contributing factor.