Peptide hormone exendin‐4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of parkinson's disease

Abstract

We investigated the effects of exendin-4 on neural stem/progenitor cells in the subventricular zone of the adult rodent brain and its functional effects in an animal model of Parkinson's disease. Our results showed expression of GLP-1 receptor mRNA or protein in the subventricular zone and cultured neural stem/progenitor cells isolated from this region. In vitro, exendin-4 increased the number of neural stem/progenitor cells, and the number of cells expressing the neuronal markers microtubule-associated protein 2, beta-III-tubulin, and neuron-specific enolase. When exendin-4 was given intraperitoneally to naïve rodents together with bromodeoxyuridine, a marker for DNA synthesis, both the number of bromodeoxyuridine-positive cells and the number of neuronal precursor cells expressing doublecortin were increased. Exendin-4 was tested in the 6-hydroxydopamine model of Parkinson's disease to investigate its possible functional effects in an animal model with neuronal loss. After unilateral lesion and a 5-week stabilization period, the rats were treated for 3 weeks with exendin-4. We found a reduction of amphetamine-induced rotations in animals receiving exendin-4 that persisted for several weeks after drug administration had been terminated. Histological analysis showed that exendin-4 significantly increased the number of both tyrosine hydroxylase- and vesicular monoamine transporter 2-positive neurons in the substantia nigra. In conclusion, our results show that exendin-4 is able to promote adult neurogenesis in vitro and in vivo, normalize dopamine imbalance, and increase the number of cells positive for markers of dopaminergic neurons in the substantia nigra in a model of Parkinson's disease.

GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism

“…Our findings indicate that the neuroprotective actions of GLP-1R agonists appear to effectively translate across a number of classic cellular and animal models, including stroke and PD, as well as cholinergic ablation (14), kainic acid-induced CA3 hippocampal loss (38), and peripheral neuropathy (35). In contrast, the Glp1r Ϫ/Ϫ mice demonstrated impaired learning, as well as increased brain injury and associated behaviors after a lesion (32).…”

“…Together, the findings of these studies suggest a loss of function in -/-mice and a physiological role for GLP-1R activation in the normal brain, as in the pancreas, that can be augmented by pharmacologic concentrations of agonists and inhibited by antagonists. Recent studies have demonstrated that Ex-4 can induce neurogenesis of neural stem cells both in culture and in the subventricular zone of rat brain after a 6-OHDA insult (38,39) and promote differentiation toward a neuronal phenotype (38), as has been reported for PC12 cells (13). Ex-4's ability to improve dopaminergic markers and function when administered a week or more after 6-OHDA-or cytokine-induced apoptosis, rather than at the time of insult as in our study, is indicative of neuroregenerative action (38,39).…”

Glucagon-Like Receptor 1 Agonists and DPP-4 Inhibitors: Potential Therapies for the Treatment of Stroke

“…3 In addition, GLP-1R activation promotes synaptic plasticity and neurite outgrow 3 and can stimulate adult neurogenesis (Figure 1). 30 The findings could form the bases for potential regenerative therapy for chronic stroke patients. At this regard, experimental data and future work are highly needed.…”

Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson’s Disease

“…Several recent discoveries have highlighted common cellular pathways that potentially relate neurodegenerative processes with abnormal mitochondrial function and abnormal glucose metabolism [2]. In parallel with these advances, a treatment for insulin resistance (exenatide; a GLP-1 agonist) has been proposed as a disease modifying drug in PD, based on multiple in vitro and in vivo studies [3][4][5][6][7][8][9].…”