Abstract
The ventral anterior nucleus of the thalamus (VATh) gathers motor information from the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr) of the basal ganglia and projects directly to motor areas of cortex. GPi/SNpr send their tonically active gamma-aminobutyric acid (GABA)ergic outputs to VATh. The abnormal firing patterns of GABAergic neurons in GPi/SNpr lead to motor deficits. In Parkinson’s disease, the spontaneous firing pattern of GPi/SNpr neurons is abnormal due to the degeneration of the nigrostriatal dopaminergic pathway. In a previous study, we found that systemically administered vasoactive intestinal peptide (VIP) was effective at reversing the motor deficits (but not the decline in striatal dopamine levels) in a rat model of Parkinson’s disease (6-hydroxydopamine (6-OHDA) exposure). In addition to the beneficial effects on the motor response, VIP could also attenuate both neuronal cell death and the characteristic loss of the myelin sheath that is associated with 6-OHDA administration into the rat striatum. VIP was thought to preserve neurons by inducing native brain mast cells to adopt a nondegranulating phenotype that had the ability to secrete numerous neuroprotective substances, such as nerve growth factor (NGF) and heparin. In the present study, the effect of systemically administered VIP (25 ng/kg i.p.) was investigated on GABA levels of the VATh, dopamine/3,4-dihydroxyphenylacetic acid (DOPAC) levels in the corpus striatum, and the NGF, rat mast cell protease II (RMCPII), serotonin, and heparin content of brain mast cells in 6-OHDA-lesioned rats. Extracellular concentrations of GABA, dopamine, and DOPAC were measured by microdialysis and high-performance liquid chromatography. NGF, RMCPII, serotonin, and heparin levels were examined by immunohistochemical staining techniques. A total of 48 young adult Sprague–Dawley rats were used in the study, and these were assigned to one of six groups. Unilateral injection of 6-OHDA, 2 µl (6 mg/µl), was made into the right corpus striatum. VIP-treated animals received 25 ng/kg VIP i.p. at 2-day intervals for a period of 15 days. The present results demonstrated that VIP significantly increased the levels of GABA in the VATh that were reduced by 6-OHDA application and increased the number of NGF-immunoreactive mast cells but did not alter dopamine metabolism. Therefore, the protective effect of VIP on motor function is possibly related to the increased levels of GABA in the VATh, and its neuroprotective actions may be mediated by the release of NGF from brain mast cells.
Similar content being viewed by others
Abbreviations
- VATh:
-
Ventral anterior nucleus of the thalamus
- GPi:
-
Internal segment of the globus pallidus
- GPe:
-
External segment of the globus pallidus
- SNpr:
-
Substantia nigra pars reticulata
- SNpc:
-
Substantia nigra pars compacta
- VIP:
-
Vasoactive intestinal peptide
- NGF:
-
Nerve growth factor
- 6-OHDA:
-
6-Hydroxydopamine
- DOPAC:
-
3,4-Dihydroxyphenylacetic acid
- RMCPII:
-
Rat mast cell protease II
- STN:
-
Subthalamic nucleus
- TB:
-
Toluidine blue
- ERK1/2/MAP kinase:
-
Extracellular signal-regulated kinase/mitogen-activated protein kinase
References
Abraham D, Oster H, Huber M, Leitges M (2007) The expression pattern of three mast cell specific proteases during mouse development. Mol Immunol 44(5):732–740
Aloe L, Skaper SD, Leon A, Levi-Montalcini R (1994) Nerve growth factor and autoimmune diseases. Autoimmunity 19(2):141–150
Bodor AL, Giber K, Rovó Z, Ulbert I, Acsády L (2008) Structural correlates of efficient GABAergic transmission in the basal ganglia–thalamus pathway. J Neurosci 28(12):3090–3102
Chen L, Yung WH (2004) GABAergic neurotransmission in globus pallidus and its involvement in neurologic disorders. Acta Physiol Sin 56(4):427–435
Delgado M, Abad C, Martinez C et al (2002) Vasoactive intestinal peptide in the immune system: potential therapeutic role in inflammatory and autoimmune. J Mol Med 80(1):16–24
Dimitriadou V, Henry P, Brochet B, Mathiau P, Aubineau P (1990) Cluster headache: ultrastructural evidence for mast cell degranulation and interaction with nerve fibres in the human temporal artery. Cephalalgia 10(5):221–228
Dimitriadou V, Pang X, Theoharides TC (2000) Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation. Int J Immunopharmacol 22(9):673–684
Duval C, Panisset M, Strafella AP, Sadikot AF (2006) The impact of ventrolateral thalamotomy on tremor and voluntary motor behavior in patients with Parkinson's disease. Exp Brain Res 170(2):160–171
Ferraro L, Tomasini MC, Fernandez M et al (2001) Nigral neurotensin receptor regulation of nigral glutamate and nigroventral thalamic GABA transmission: a dual-probe microdialysis study in intact conscious rat brain. Neuroscience 102(1):113–120
Galeffi F, Bianchi L, Bolam JP, Della Corte CL (2003) The effect of 6-hydroxydopamine lesions on the release of amino acids in the direct and indirect pathways of the basal ganglia: a dual microdialysis probe analysis. Eur J NeuroSci 18(4):856–868
Galvan A, Wichmann T (2008) Pathophysiology of parkinsonism. Clin Neurophysiol 119(7):1459–1474
Gerfen CR (2006) Indirect-pathway neurons lose their spines in Parkinson disease. Nat Neurosci 9(2):157–158
Gerfen CR, Miyachi S, Paletzki R, Brown P (2002) D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase. J Neurosci 22(12):5042–5054
Gonzalez-Rey E, Chorny A, Fernandez-Martin A, Varela N, Delgado M (2005) Vasoactive intestinal peptide family as a therapeutic target for Parkinson's disease. Expert Opin Ther Targets 9(5):923–929
Hashitani T, Mizukawa K, Kumazaki M, Nishino H (1998) Dopamine metabolism in the striatum of hemiparkinsonian model rats with dopaminergic grafts. Neurosci Res 30(1):43–52
Hauber W (1998) Involvement of basal ganglia transmitter systems in movement initiation. Prog Neurobiol 56(5):507–540
Hossain MA, Weiner N (1995) Interactions of dopaminergic and GABAergic neurotransmission: impact of 6-hydroxydopamine lesions into the substantia nigra of rats. J Pharmacol Exp Ther 275(1):237–244
Leon A, Buriani A, Dal Toso R et al (1994) Mast cells synthesize, store, and release nerve growth factor. Proc Natl Acad Sci USA 91(9):3739–3743
Lévesque M, Parent A (2005) The striatofugal fiber system in primates: a reevaluation of its organization based on single-axon tracing studies. Proc Natl Acad Sci USA 102(33):11888–11893
Marshall JS, Stead RH, McSharry C, Nielsen L, Bienenstock J (1990) The role of mast cell degranulation products in mast cell hyperplasia. I. Mechanism of action of nerve growth factor. J Immunol 144(5):1886–1892
Micera A, De Simone R, Aloe L (1995) Elevated levels of nerve growth factor in the thalamus and spinal cord of rats affected by experimental allergic encephalomyelitis. Arch Ital Biol 133(2):131–142
Miller HR, Pemberton AD (2002) Tissue-specific expression of mast cell granule serine proteinases and their role in inflammation in the lung and gut. Immunology 105(4):375–390
Nadjar A, Brotchie JM, Guigoni C et al (2006) Phenotype of striatofugal medium spiny neurons in parkinsonian and dyskinetic nonhuman primates: a call for a reappraisal of the functional organization of the basal ganglia. J Neurosci 26(34):8653–8661
O'Connor WT (1998) Functional neuroanatomy of the basal ganglia as studied by dual-probe microdialysis. Nucl Med Biol 25(8):743–746
Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic, New York
Purves D, Augustine GJ, Fıtzpatrick D et al (2004) Movement and its central control, neuroscience, 3rd edn. Sinauer Associates, Sunderland, pp 417–434
Rangel-Barajas C, Silva I, García-Ramírez M et al (2008) 6-OHDA-induced hemiparkinsonism and chronic L-DOPA treatment increase dopamine D1-stimulated [(3)H]-GABA release and [(3)H]-cAMP production in substantia nigra pars reticulata of the rat. Neuropharmacology 55:704–711
Robertson RG, Graham WC, Sambrook MA, Crossman AR (1991) Further investigations into the pathophysiology of MPTP-induced parkinsonism in the primate: an intracerebral microdialysis study of gamma-aminobutyric acid in the lateral segment of the globus pallidus. Brain Res 563(1–2):278–280
Rouleau A, Dimitriadou V, Trung Tuong MD et al (1997) Mast cell specific proteases in rat brain: changes in rats with experimental allergic encephalomyelitis. J Neural Transm 104(4–5):399–417
Said SI (1986) Vasoactive intestinal peptide. J Endocrinol Invest 9:191–200
Segovia J, Tossman U, Herrera-Marschitz M, Garcia-Munoz M, Ungerstedt U (1986) Gamma-aminobutyric acid release in the globus pallidus in vivo after a 6-hydroxydopamine lesion in the substantia nigra of the rat. Neurosci Lett 70(3):364–368
Sil'kis IG (2002) A possible mechanism for the dopamine-evoked synergistic disinhibition of thalamic neurons via the “direct” and “indirect” pathways in the basal ganglia. Neurosci Behav Physiol 32(3):205–212
Skaper SD, Pollock M, Facci L (2001) Mast cells differentially express and release active high molecular weight neurotrophins. Brain Res Mol Brain Res 97(2):177–185
Soghomonian JJ, Laprade N (1997) Glutamate decarboxylase (GAD67 and GAD65) gene expression is increased in a subpopulation of neurons in the putamen of Parkinsonian monkeys. Synapse 27(2):122–132
Staun-Olsen P, Ottesen B, Gammeltoft S, Fahrenkrug J (1985) The regional distribution of receptors for vasoactive intestinal polypeptide (VIP) in the rat central nervous system. Brain Res 330(2):317–321
Tachibana Y, Kita H, Chiken S, Takada M, Nambu A (2008) Motor cortical control of internal pallidal activity through glutamatergic and GABAergic inputs in awake monkeys. Eur J NeuroSci 27(1):238–253
Tunçel N, Sener E, Cerit C et al (2005) Brain mast cells and therapeutic potential of vasoactive intestinal peptide in a Parkinson's disease model in rats: brain microdialysis, behavior, and microscopy. Peptides 26(5):827–836
Wang HL, Li A, Wu T (1997) Vasoactive intestinal polypeptide enhances the GABAergic synaptic transmission in cultured hippocampal neurons. Brain Res 746(1–2):294–300
Welle M (1997) Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase. J Leukoc Biol. 61(3):233–245
Acknowledgments
We would like to thank Dr. Luigi Aloe, Institute of Neurobiology and Molecular Medicine, National Research Council, NGF Section, Via Del Fosso di Fiorano 64, 00143, Rome, Italy, who kindly donated the NGF antibody.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Korkmaz, O.T., Tunçel, N., Tunçel, M. et al. Vasoactive Intestinal Peptide (VIP) Treatment of Parkinsonian Rats Increases Thalamic Gamma-Aminobutyric Acid (GABA) Levels and Alters the Release of Nerve Growth Factor (NGF) by Mast Cells. J Mol Neurosci 41, 278–287 (2010). https://doi.org/10.1007/s12031-009-9307-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-009-9307-3