Alexander Harkavyi

Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection

Glucagon‐like peptide 1 (GLP‐1) is a relatively recently discovered molecule originating in the so‐called L‐cells of the intestine. The peptide has insulinotrophic properties and it is this characteristic that has predominantly been investigated. This has led to the use of the GLP‐1‐like peptide exendin‐4 (EX‐4), which has a much longer plasma half‐life than GLP‐1 itself, being used in the treatment of type II diabetes. The mode of action of this effect appears to be a reduction in pancreatic apoptosis, an increase in beta cell proliferation or both. Thus, the effects of GLP‐1 receptor stimulation are not based upon insulin replacement but an apparent repair of the pancreas. Similar data suggest that the same effects may occur in other peripheral tissues. More recently, the roles of GLP‐1 and EX‐4 have been studied in nervous tissue. As in the periphery, both peptides appear to promote cellular growth and reduce apoptosis. In models of Alzheimers disease, Parkinsons disease and peripheral neuropathy, stimulation of the GLP‐1 receptor has proved to be highly beneficial. In the case of Parkinsons disease this effect is evident after the neurotoxic lesion is established, suggesting real potential for therapeutic use. In the present review we examine the current status of the GLP‐1 receptor and its potential as a therapeutic target.

Dopamine-Dependent Tuning of Striatal Inhibitory Synaptogenesis

Dopaminergic projections to the striatum, crucial for the correct functioning of this brain region in adulthood, are known to be established early in development, but their role is currently uncharacterized. We demonstrate here that dopamine, by activating D1- and/or D2-dopamine receptors, decreases the number of functional GABAergic synapses formed between the embryonic precursors of the medium spiny neurons, the principal output neurons of the striatum, with associated changes in spontaneous synaptic activity. Activation of these receptors reduces the size of postsynaptic GABAA receptor clusters and their overall cell-surface expression, without affecting the total number of clusters or the size or number of GABAergic nerve terminals. These changes result from an increased internalization of GABAA receptors, and are mediated by distinct signaling pathways converging at the level of GABAA receptors to cause a transient PP2A/PP1-dependent dephosphorylation. Thus, tonic D1- and D2-receptor activity limits the extent of collateral inhibitory synaptogenesis between medium spiny neurons, revealing a novel role of dopamine in controlling the development of intrinsic striatal microcircuits.

Retracted: Exendin-4 reverts behavioural and neurochemical dysfunction in a pre-motor rodent model of Parkinson's disease with noradrenergic deficit

BACKGROUND AND PURPOSE Parkinsons disease (PD) is characterized by progressive dopaminergic cell loss; however, the noradrenergic system exhibits degeneration as well. Noradrenergic deficit in PD may be responsible for certain non‐motor symptoms of the pathology, including psychiatric disorders and cognitive decline. The aim of this study was to generate a pre‐motor rodent model of PD with noradrenergic denervation, and to assess whether treatment with exendin‐4 (EX‐4), a glucagon‐like peptide 1 receptor agonist, could reverse impairment exhibited by our model.

The CRF-like peptide urocortin greatly attenuates loss of extracellular striatal dopamine in rat models of Parkinson's disease by activating CRF(1) receptors.

We have recently observed that the corticotrophin releasing factor (CRF) related peptide urocortin reverses key features of nigrostriatal damage in two paradigms of Parkinsons disease. Here we have studied whether these effects are supported by a retention of striatal basal and evoked extracellular dopamine and the receptor(s) that may mediate this effect. Fourteen days following stereotaxic injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) and urocortin, extracellular dopamine levels in striata ipsilateral to injection sites of 6-OHDA/LPS and urocortin treated rats were comparable with sham injected rats, whilst rats given 6-OHDA/LPS and vehicle had considerably lower dopamine levels. Striatal dopamine levels in animals where urocortin injection was delayed by seven days were only modestly decreased compared to animals receiving 6-OHDA/LPS and urocortin concomitantly. Additionally, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also preserved in dialysates from urocortin treated rats. The effects of urocortin were entirely blocked by the non-selective CRF receptor antagonist alpha-helical CRF as well as the selective CRF(1) antagonist NBI 27914 and were not replicated by the selective CRF(2) ligand urocortin III. In the substantia nigra tissue dopamine changes mirrored those seen in striatal extracellular dopamine. Our data strongly suggest that urocortin is capable of maintaining adequate nigrostriatal function in vivo via CRF(1) receptors following. neurotoxic challenge.

The CRF-like peptide urocortin produces a long-lasting recovery in rats made hemiparkinsonian by 6-hydroxydopamine or lipopolysaccharide.

We have recently observed that the corticotropin releasing factor related peptide urocortin (UCN) reverses key features of nigrostriatal neurodegeneration following intracerebral injection of either 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS). To determine the potential therapeutic utility of UCN here we have studied whether these effects are sustained for several weeks following peptide injection. In addition we have studied whether UCN still shows efficacy in rats with more pronounced nigrostriatal lesions. Rats were lesioned using 6-OHDA or LPS and injected with UCN either 7 or 14 days later. At different time points animals were tested for rotational behaviour (apomorphine, 0.5 mg/kg) and subsequently implanted with bilateral dialysis probes into the striata. The following day rats were dialysed to estimate extracellular striatal dopamine (DA) and then sacrificed for estimation of striatal tissue DA and subsequent immunohistochemistry of TH(+) cells in the substantia nigra (SN). Toxin treated rats given UCN 7 days later showed clear evidence of reduced nigrostriatal damage both 28 and 84 days following UCN compared with saline injection. In rats given UCN 14 days after toxin injection, by which time deficits were maximal, a restoration of nigrostriatal damage was observed. This suggests that UCN is able to elicit a sustained restoration of functional nigrostriatal integrity and has the ability to produce a recovery in severely lesioned rats. These findings suggest that stimulation of CRF (probably CRF(1)) receptors could have therapeutic utility in PD.

Exendin-4 treatment enhances L-DOPA evoked release of striatal dopamine and decreases dyskinetic movements in the 6-hydoxydopamine lesioned rat

Objectives  To determine whether the glucagon‐like 1 peptide analogue exendin‐4 (EX‐4) augments the neurochemical effects of a single L‐DOPA treatment and whether EX‐4 can decrease L‐DOPA induced dyskinesias (LIDS).

Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra.

Glucagon-like peptide-1 receptor (GLP-1R) activation by exendin-4 (EX-4) is effective in preclinical models of Parkinsons disease (PD) and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN). We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39) as well as the potential role of dopamine (DA) D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39) or nafadotride (D3 antagonist) and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39) and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39) or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39) or NAF, while in the SN the opposite profile was seen.