Abstract
In the present study, the effectiveness of glucose-dependent insulinotropic polypeptide (GIP) was evaluated by behavioral tests in 6-hydroxydopamine (6-OHDA) hemi-parkinsonian (PD) rats. Pharmacokinetic measurements of GIP were carried out at the same dose studied behaviorally, as well as at a lower dose used previously. GIP was delivered by subcutaneous administration (s.c.) using implanted ALZET micro-osmotic pumps. After two days of pre-treatment, male Sprague Dawley rats received a single unilateral injection of 6-OHDA into the medial forebrain bundle (MFB). The neuroprotective effects of GIP were evaluated by apomorphine-induced contralateral rotations, as well as by locomotor and anxiety-like behaviors in open-field tests. Concentrations of human active and total GIP were measured in plasma during a five-day treatment period by ELISA and were found to be within a clinically translatable range. GIP pretreatment reduced behavioral abnormalities induced by the unilateral nigrostriatal dopamine (DA) lesion produced by 6-OHDA, and thus may be a novel target for PD therapeutic development.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by symptoms related to progressive dopamine neuron loss within the substantia nigra pars compacta [1]
We report the efficacy of glucose-dependent insulinotropic polypeptide (GIP) in a rat model of PD induced by intracranial unilateral injection of the neurotoxin 6-OHDA, using behavioral tests
Body weight: Repeated-measures ANOVA showed a significant effect of time (F(5, 100) = 89.650, p < 0.001) and a treatment × time interaction (F(1, 20) = 8661.285, p < 0.001), in rats one week after the 6-OHDA lesion
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by symptoms related to progressive dopamine neuron loss within the substantia nigra pars compacta [1]. Previous research has demonstrated that treatment with glucagon-like peptide-1 (GLP-1), an endogenous incretin, as well as long-acting GLP-1 analogues, provide neurotrophic and neuroprotective actions in many acute and chronic neurodegenerative models through GLP-1 receptor (R) activation within the brain [4]. The activation of the GLP-1R on neurons induces potent neurotrophic and neuroprotective actions in cellular and animal models of neural injury and neurodegeneration [5,6,7,8,9,10], including models of PD [7,11,12]. GLP-1 receptor (GLP-1R) agonists have demonstrated favorable activity in cellular and animal models of PD [5,13,14]. There is an ongoing clinical trial with the nonhydrolyzable GLP-1 agonist Ex-4 in Parkinson’s disease [15,16]
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