<p>A Novel Octapeptide Derived From G Protein-Coupled Receptor 124 Improves Cognitive Function Via Pro-Angiogenesis In A Rat Model Of Chronic Cerebral Hypoperfusion-Induced Vascular Dementia</p>

Background: In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target. Methods: We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies. Results: Knockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an “overload” hypothesis for the etiology of the psychiatric symptoms of Parkinson disease. Limitations: Behavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types. Conclusion: GPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.

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The effect of intra-striatal administration of GPR55 agonist (LPI) and antagonist (ML193) on sensorimotor and motor functions in a Parkinson’s disease rat model

Acta Neuropsychiatrica ◽

10.1017/neu.2020.30 ◽

2020 ◽

pp. 1-7

Author(s):

Iman Fatemi ◽

Abbas Abdollahi ◽

Ali Shamsizadeh ◽

Mohammad Allahtavakoli ◽

Ali Roohbakhsh

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Locomotor Activity ◽

G Protein ◽

Rat Model ◽

Field Tests ◽

Motor Deficits ◽

G Protein Coupled Receptor ◽

Motor Functions ◽

G Protein Coupled

Abstract Objective: G protein-coupled receptor 55 (GPR55) is an orphan G protein-coupled receptor with various physiological functions. Recent evidence suggests that this receptor may be involved in the control of motor functions. Therefore, in the present study, we evaluated the effects of intra-striatal administration of GPR55 selective ligands in a rat model of Parkinson’s disease. Methods: Experimental Parkinson was induced by unilateral intra-striatal administration of 6-hydroxydopamine (6-OHDA, 10 µg/rat). L-α-lysophosphatidylinositol (LPI, 1 and 5 µg/rat), an endogenous GPR55 agonist, and ML193 (1 and 5 µg/rat), a selective GPR55 antagonist, were injected into the striatum of 6-OHDA-lesioned rats. Motor performance and balance skills were evaluated using the accelerating rotating rod and the ledged beam tests. The sensorimotor function of the forelimbs and locomotor activity were assessed by the adhesive removal and open field tests, respectively. Results: 6-OHDA-lesioned rats had impaired behaviours in all tests. Intra-striatal administration of LPI in 6-OHDA-lesioned rats increased time on the rotarod, decreased latency to remove the label, with no significant effect on slip steps, and locomotor activity. Intra-striatal administration of ML193 also increased time on the rotarod, decreased latency to remove the label and slip steps in 6-OHDA-lesioned rats mostly at the dose of 1 µg/rat. Conclusions: This study suggests that the striatal GPR55 is involved in the control of motor functions. However, considering the similar effects of GPR55 agonist and antagonist, it may be concluded that this receptor has a modulatory role in the control of motor deficits in an experimental model of Parkinson.

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