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

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 microl (6 mg/microl), 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.

The Effects of Neurotrophins and the Neuropeptides VIP and PACAP on HIV-1 Infection: Histories with Opposite Ends

“…For example, in a rat model of Parkinson's disease, VIP protects motor functions by inducing, among other mechanisms, NGF release from brain mast cells [192]; likewise, VIP enhances NGF gene expression and the release of both precursor and mature NGFs in human keratinocytes [193]. PACAP induces the expression of the NGF TrkA receptor via PAC1 activation [194] and can also transactivate the TrkA receptor in both neurons and monocytes [195,196,197], thus triggering TrkA receptor-related signaling pathways.…”

Antioxidant and Anti-Apoptotic Activity of Vasoactive Intestinal Peptide (VIP) Against 6-Hydroxy Dopamine Toxicity in the Rat Corpus Striatum

“…6-Hydroxy dopamine (6-OHDA) was the first dopaminergic neurotoxin discovered and has been used in models of PD (Schober 2004;Bové et al 2005;Tunçel et al 2005;Korkmaz et al 2010). 6-OHDA, a prototypic oxidative stress neurotoxin, is oxidized in neurons causing respiratory inhibition, and it induces free radical formation and oxidative stress (Schober 2004;Bové et al 2005).…”

“…These effects, along with VIP's anti-glutamatergic function, have been well documented in various tissues, including neural tissue, and in pathological conditions such as PD, septic shock, hemorrhagic shock, rheumatoid arthritis, acute respiratory distress syndrome, ischemic-reperfused retina, and brain trauma (Tunçel et al 1996(Tunçel et al , 1997(Tunçel et al , 1998(Tunçel et al , 2005Delgado and Ganea 2003a;Can et al 2004;Gonzalez-Rey et al 2005;Korkmaz et al 2010). VIP can also cross the blood-brain barrier (BBB; Dogrukol-Ak et al 2003).…”

“…VIP was also thought to preserve neurons by inducing native brain mast cells (Tunçel et al 2005;Korkmaz et al 2010). Although VIP reversed the motor deficits, it did not alter the reduction of striatal dopamine levels nor the increase in dopamine turnover.…”

“…The beneficial effect of VIP on motor function is likely due to improved GABA levels in the ventral anterior thalamus (VATh). The release of nerve growth factor from brain mast cells mediated the neuroprotective action of VIP (Korkmaz et al 2010). Even though the antioxidant and anti-apoptotic role of VIP has been shown in various tissues and pathological conditions, there have been no studies demonstrating VIP function in the corpus striatum of 6-OHDA-lesioned rats.…”