Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Metabolic Brain Disease
Published in: Metabolic Brain Disease 4/2016

01-08-2016 | Original Article

Behavioural effects of basal ganglia rho-kinase inhibition in the unilateral 6-hydroxydopamine rat model of Parkinson’s disease

Authors: Salim Yalcin Inan, Burak Cem Soner, Ayse Saide Sahin

Published in: Metabolic Brain Disease | Issue 4/2016

Login to get access

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, which affects more than six million people in the world. While current available pharmacological therapies for PD in the early stages of the disease usually improve motor symptoms, they cause side effects, such as fluctuations and dyskinesias in the later stages. In this later stage, high frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option which is most successful to treat drug resistant advanced PD. It has previously been demonstrated that activation of Rho/Rho-kinase pathway is involved in the dopaminergic cell degeneration which is one of the main characteristics of PD pathology. In addition, the involvement of this pathway has been suggested in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However, up to date, to our knowledge there are no previous reports showing the beneficial effects of the potent Rho-kinase inhibitor Y-27632 in the 6-hydroxydopamine (6-OHDA) rat model of PD. Therefore, in the present study, we investigated the behavioural effects of basal ganglia Y-27632 microinjections in this PD model. Our results indicated that basal ganglia Y-27632 microinjections significantly decreased the number of contralateral rotations-induced by apomorphine, significantly increased line crossings in the open-field test, contralateral forelimb use in the limb-use asymmetry test and contralateral tape playing time in the somatosensory asymmetry test, which may suggest that Y-27632 could be a potentially active antiparkinsonian agent.
Literature
Ahn DK, Lee SY, Han SR, Ju JS, Yang GY, Lee MK, Youn DH, Bae YC (2009) Intratrigeminal ganglionic injection of LPA causes neuropathic pain-like behavior and demyelination in rats. Pain 146:114–120CrossRefPubMed
Benabid AL, Chabardes S, Mitrofanis J, Pollak P (2009) Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 8:67–81CrossRefPubMed
Bezard E, Brotchie JM, Gross CE (2001) Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci 2:577–588CrossRefPubMed
Blandini F, Armentero MT, Martignoni E (2008) The 6-hydroxydopamine model: news from the past. Parkinsonism Relat Disord 14(Suppl 2):S124–S129CrossRefPubMed
Borrajo A, Rodriguez-Perez AI, Villar-Cheda B, Guerra MJ, Labandeira-Garcia JL (2014) Inhibition of the microglial response is essential for the neuroprotective effects of rho-kinase inhibitors on MPTP-induced dopaminergic cell death. Neuropharmacology 85C:1–8CrossRef
Buyukafsar K, Yalcin I, Kurt AH, Tiftik RN, Sahan-Firat S, Aksu F (2006) Rho-kinase inhibitor, Y-27632, has an antinociceptive effect in mice. Eur J Pharmacol 541:49–52CrossRefPubMed
Castro-Alvarez JF, Gutierrez-Vargas J, Darnaudery M, Cardona-Gomez GP (2011) ROCK inhibition prevents tau hyperphosphorylation and p25/CDK5 increase after global cerebral ischemia. Behav Neurosci 125:465–472CrossRefPubMed
Chan CC, Khodarahmi K, Liu J, Sutherland D, Oschipok LW, Steeves JD, Tetzlaff W (2005) Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury. Exp Neurol 196:352–364CrossRefPubMed
Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease: a review. JAMA 311:1670–1683CrossRefPubMed
Dash PK, Orsi SA, Moody M, Moore AN (2004) A role for hippocampal rho-ROCK pathway in long-term spatial memory. Biochem Biophys Res Commun 322:893–898CrossRefPubMed
Denheyer M, Kiss ZH, Haffenden AM (2009) Behavioral effects of subthalamic deep brain stimulation in Parkinson’s disease. Neuropsychologia 47:3203–3209CrossRefPubMed
Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD, McKerracher L (2002) Rho signaling pathway targeted to promote spinal cord repair. J Neurosci 22:6570–6577PubMed
Deumens R, Blokland A, Prickaerts J (2002) Modeling Parkinson’s disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 175:303–317CrossRefPubMed
Dubreuil CI, Marklund N, Deschamps K, McIntosh TK, McKerracher L (2006) Activation of rho after traumatic brain injury and seizure in rats. Exp Neurol 198:361–369CrossRefPubMed
Fleming SM, Schallert T, Ciucci MR (2012) Cranial and related sensorimotor impairments in rodent models of Parkinson’s disease. Behav Brain Res 231:317–322CrossRefPubMed
Geiger, BM, Frank, LE, Caldera-Siu, AD, Pothos, EN (2008) Survivable stereotaxic surgery in rodents. J Vis Exp doi:10.​3791/​880
Ghosh B, Antonio T, Reith ME, Dutta AK (2010) Discovery of 4-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)Ethyl)piperaz in-1-yl)quinolin-8-ol and its analogues as highly potent dopamine D2/D3 agonists and as iron chelator: in vivo activity indicates potential application in symptomatic and neuroprotective therapy for Parkinson’s disease. J Med Chem 53:2114–2125CrossRefPubMedPubMedCentral
Glajch KE, Fleming SM, Surmeier DJ, Osten P (2012) Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson’s disease. Behav Brain Res 230:309–316CrossRefPubMed
Günther R, Saal KA, Suhr M, Scheer D, Koch JC, Bähr M, Lingor P, Tönges L (2014) The rho kinase inhibitor Y-27632 improves motor performance in male SOD1-G93A mice. Front Neurosci 8:304PubMedPubMedCentral
Henderson JM, Dunnett SB (1998) Targeting the subthalamic nucleus in the treatment of Parkinson’s disease. Brain Res Bull 46:467–474CrossRefPubMed
Inan SY, Soner BC, Sahin AS (2015) Infralimbic cortex rho-kinase inhibition causes antidepressant-like activity in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 57:36–43CrossRef
Ito K, Hirooka Y, Sakai K, Kishi T, Kaibuchi K, Shimokawa H, Takeshita A (2003) Rho/rho-kinase pathway in brain stem contributes to blood pressure regulation via sympathetic nervous system: possible involvement in neural mechanisms of hypertension. Circ Res 92:1337–1343CrossRefPubMed
Ito K, Hirooka Y, Hori N, Kimura Y, Sagara Y, Shimokawa H, Takeshita A, Sunagawa K (2005) Inhibition of rho-kinase in the nucleus tractus solitarius enhances glutamate sensitivity in rats. Hypertension 46:360–365CrossRefPubMed
Kim SJ, Jeon S, Shin EY, Kim EG, Park J, Bae CD (2004) AMPA, not NMDA, activates RhoA GTPases and subsequently phosphorylates moesin. Exp Mol Med 36:98–102CrossRefPubMed
Kirik D, Rosenblad C, Bjorklund A (1998) Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol 152:259–277CrossRefPubMed
Kirik D, Rosenblad C, Bjorklund A, Mandel RJ (2000) Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson’s model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J Neurosci 20:4686–4700PubMed
Kucuk A, Golgeli A, Saraymen R, Koc N (2008) Effects of age and anxiety on learning and memory. Behav Brain Res 195:147–152CrossRefPubMed
Li M, Huang Y, Ma AA, Lin E, Diamond MI (2009) Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice. Neurobiol Dis 36:413–420CrossRefPubMed
Loirand G, Sauzeau V, Pacaud P (2013) Small G proteins in the cardiovascular system: physiological and pathological aspects. Physiol Rev 93:1659–1720CrossRefPubMed
Miklyaeva EI, Castaneda E, Whishaw IQ (1994) Skilled reaching deficits in unilateral dopamine-depleted rats: impairments in movement and posture and compensatory adjustments. J Neurosci 14:7148–7158PubMed
Mueller BK, Mack H, Teusch N (2005) Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 4:387–398CrossRefPubMed
Narita M, Takagi M, Aoki K, Kuzumaki N, Suzuki T (2003) Implication of rho-associated kinase in the elevation of extracellular dopamine levels and its related behaviors induced by methamphetamine in rats. J Neurochem 86:273–282CrossRefPubMed
Ota KT, Monsey MS, Wu MS, Schafe GE (2010) Synaptic plasticity and NO-cGMP-PKG signaling regulate pre- and postsynaptic alterations at rat lateral amygdala synapses following fear conditioning. PLoS One 5:e11236CrossRefPubMedPubMedCentral
Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia. II. the place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain Res Rev 20:128–154CrossRefPubMed
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego
Rauch F, Schwabe K, Krauss JK (2010) Effect of deep brain stimulation in the pedunculopontine nucleus on motor function in the rat 6-hydroxydopamine Parkinson model. Behav Brain Res 210:46–53CrossRefPubMed
Rodriguez-Perez AI, Dominguez-Meijide A, Lanciego JL, Guerra MJ, Labandeira-Garcia JL (2013) Inhibition of rho kinase mediates the neuroprotective effects of estrogen in the MPTP model of Parkinson’s disease. Neurobiol Dis 58:209–219CrossRefPubMed
Saitoh A, Yamada M, Yamada M, Kobayashi S, Hirose N, Honda K, Kamei J (2006) ROCK inhibition produces anxiety-related behaviors in mice. Psychopharmacology 188:1–11CrossRefPubMed
Sanchez M, Gastaldi L, Remedi M, Caceres A, Landa C (2008) Rotenone-induced toxicity is mediated by rho-GTPases in hippocampal neurons. Toxicol Sci 104:352–361CrossRefPubMed
Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39:777–787CrossRefPubMed
Schober A (2004) Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP. Cell Tissue Res 318:215–224CrossRefPubMed
Schubert V, Da Silva JS, Dotti CG (2006) Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor-dependent manner. J Cell Biol 172:453–467CrossRefPubMedPubMedCentral
Schwarting RK, Huston JP (1996) The unilateral 6-hydroxydopamine lesion model in behavioral brain research. analysis of functional deficits, recovery and treatments. Prog Neurobiol 50:275–331CrossRefPubMed
Shi J, Wei L (2013) Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol 62:341–354CrossRefPubMed
Sughrue ME, Mocco J, Komotar RJ, Mehra A, D’Ambrosio AL, Grobelny BT, Penn DL, Connolly ES Jr. (2006) An improved test of neurological dysfunction following transient focal cerebral ischemia in rats. J Neurosci Methods 151:83–89CrossRefPubMed
Sweetat S, Rosenblum K, Lamprecht R (2012) Rho-associated kinase in the gustatory cortex is involved in conditioned taste aversion memory formation but not in memory retrieval or relearning. Neurobiol Learn Mem 97:1–6CrossRefPubMed
Tatenhorst L, Tonges L, Saal KA, Koch JC, Szego EM, Bahr M, Lingor P (2014) Rho kinase inhibition by fasudil in the striatal 6-hydroxydopamine lesion mouse model of Parkinson disease. J Neuropathol Exp Neurol 73:770–779CrossRefPubMed
Tonges L, Frank T, Tatenhorst L, Saal KA, Koch JC, Szego EM, Bahr M, Weishaupt JH, Lingor P (2012) Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease. Brain 135:3355–3370CrossRefPubMedPubMedCentral
Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367:69–93CrossRefPubMed
Ungerstedt U, Arbuthnott GW (1970) Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 24:485–493CrossRefPubMed
Vesterinen HM, Currie GL, Carter S, Mee S, Watzlawick R, Egan KJ, Macleod MR, Sena ES (2013) Systematic review and stratified meta-analysis of the efficacy of RhoA and rho kinase inhibitors in animal models of ischaemic stroke. Syst Rev 2:33CrossRefPubMedPubMedCentral
Volke V, Soosaar A, Koks S, Bourin M, Mannisto PT, Vasar E (1997) 7-nitroindazole, a nitric oxide synthase inhibitor, has anxiolytic-like properties in exploratory models of anxiety. Psychopharmacology 131:399–405CrossRefPubMed
Wu BQ, Bi ZG, Qi Q (2013) Inactivation of the rho-ROCK signaling pathway to promote neurologic recovery after spinal cord injuries in rats. Chin Med J 126:3723–3727PubMed
Metadata
Title
Behavioural effects of basal ganglia rho-kinase inhibition in the unilateral 6-hydroxydopamine rat model of Parkinson’s disease
Authors
Salim Yalcin Inan
Burak Cem Soner
Ayse Saide Sahin
Publication date
01-08-2016
Publisher
Springer US
Published in
Metabolic Brain Disease / Issue 4/2016
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI
https://doi.org/10.1007/s11011-016-9820-3

Other articles of this Issue 4/2016

Metabolic Brain Disease 4/2016 Go to the issue

Original Article

Cerebral blood flow changes in hemodialysis and peritoneal dialysis patients: an arterial-spin labeling MR imaging

Original Article

Maternal seizures can affect the brain developing of offspring

Original Article

Meloxicam-loaded nanocapsules as an alternative to improve memory decline in an Alzheimer’s disease model in mice: involvement of Na+, K+-ATPase

Original Article

Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer’s disease via SIRT1/NF-κB pathway

Original Article

Pharmacological evidence of neuro-pharmacological activity of Acacia tortilis leaves in mice

Original Article

Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice