Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease

We have recently observed that the corticotrophin releasing hormone (CRF) related peptide urocortin (UCN) reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS) neuroinflammatory paradigm of Parkinson's disease (PD). To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA) and also tyrosine hydroxylase (TH) activity. Fourteen days following intranigral injections of LPS and UCN, rats showed only modest circling after DA receptor stimulation with apomorphine, in contrast to those given LPS and vehicle where circling was pronounced. In separate experiments, rats received UCN seven days following LPS, and here apomorphine challenge caused near identical circling intensity to those that received LPS and UCN concomitantly. In a similar and consistent manner with the preservation of motor function, UCN 'protected' the nigra from both DA depletion and loss of TH activity, indicating preservation of DA cells. The effects of UCN were antagonised by the non-selective CRF receptor antagonist α-helical CRF and were not replicated by the selective CRF2 ligand UCN III. This suggests that UCN is acting via CRF1 receptors, which have been shown to be anti-inflammatory in the periphery. Our data therefore indicate that UCN is capable of maintaining adequate nigrostriatal function in vivo, via CRF1 receptors following a neuro-inflammatory challenge. This has potential therapeutic implications in PD

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD.</p> <p>Methods</p> <p>Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated <it>in vivo </it>and <it>ex vivo </it>with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system.</p> <p>Results</p> <p>EX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats.</p> <p>Conclusion</p> <p>The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in current clinical use in the management of type-II diabetes and freely crosses the blood brain barrier; hence, assessment of the clinical efficacy of EX-4 in patients with PD could be pursued without delay.</p

Nitric oxide regulates excitatory amino acid release in a biphasic manner in freely moving rats

The effect of altering hippocampal nitric oxide levels on basal and N-methyl-d-aspartate (NMDA) receptor-evoked release of glutamate and aspartate has been studied in freely moving rats. NMDA increased extracellular glutamate and aspartate in a concentration-dependent manner. The nitric oxide synthase inhibitor l-nitro-arginine-methyl ester (l-NAME; 100 μM) increased basal glutamate and aspartate release, and also enhanced release of these amino acids evoked by NMDA (100 μM) compared with the same concentration of NMDA infused alone. l-NAME at 200 μM increased basal dialysate glutamate, but not aspartate, to a lesser extent than the 100 μM concentration of the drug, and the NMDA-induced release of glutamate and aspartate was decreased. l-NAME at 1.0 mM did not significantly alter basal extracellular glutamate but significantly decreased dialysate aspartate, while abolishing the NMDA-evoked release of both amino acids. The actions of l-NAME were not mimicked by its much less active isomer d-nitro-arginine-methyl ester. The nitric oxide donor drug S-nitroso-N-penicillamine decreased dialysate glutamate and aspartate at a 500 μM concentration but increased the extracellular level of both amino acids when infused at 1.0 mM and 2.0 mM concentrations. These data suggest that nitric oxide may mediate both excitatory and inhibitory functions, according to the level of nitric oxide production in vivo

Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo

The effect of altering hippocampal nitric oxide (NO) levels on basal and N-methyl-d-aspartate receptor-evoked release of GABA has been studied in freely moving rats. N-Methyl-d-aspartate (NMDA) increased extracellular GABA in a concentration-dependent manner. The nitric oxide synthase inhibitor t-nitro-arginine-methyl ester (l-NAME; 100 μM) increased basal GABA release, and also enhanced release of GABA evoked by NMDA (100 μM) compared with the same concentration of NMDA infused alone. 200 μM l-NAME increased basal dialysate GABA, but to a lesser extent than the 100 μM concentration of the drug, and the NMDA-induced release of GABA was decreased. 1.0 MM l-NAME significantly decreased basal extracellular GABA, while abolishing the NMDA-evoked release of the amino acid. The actions of l-NAME were not mimicked by its much less active isomer d-nitro-arginine-methyl ester. The NO donor S-nitroso-N-acetylpenicillamine decreased dialysate GABA at a 500 μM concentration but increased the extracellular level of the transmitter when infused at 1.0 and 2.0 mM concentrations. These data suggest that NO may mediate both excitatory and inhibitory functions in vivo

Association between self-reported eating rate, energy intake, and cardiovascular risk factors in a multi-ethnic asian population

10.3390/nu12041080Nutrients124108