ABSTRACT
Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson's disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.
Subject(s)
Adenosine A2 Receptor Antagonists , Corpus Striatum , Disease Models, Animal , Parkinson Disease , Receptor, Adenosine A2A , Animals , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/therapeutic use , Rats , Male , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Receptor, Adenosine A2A/metabolism , Corpus Striatum/metabolism , Corpus Striatum/drug effects , Corpus Striatum/pathology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Triazoles/pharmacology , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Substantia Nigra/pathology , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: This study aimed to assess the intraexaminer and interexaminer reproducibility of the Downing test in sacroiliac joint evaluation in symptomatic and asymptomatic individuals. METHODS: A reliability study was conducted with a test-retest design in 54 college students of both sexes. To assess the intraexaminer reproducibility, each participant was evaluated twice by the same examiner with a 7-day interval, and to assess the interexaminer reproducibility, each participant was evaluated by 2 examiners. RESULTS: Of the 54 participants included in the study, 18 (33.3%) were asymptomatic and 36 (66.7%) were symptomatic; a total of 108 sacroiliac joints were evaluated. Sacroiliac joint diagnosis based on the Downing test presented low intraexaminer reproducibility in all participants (κ = 0.12, 95% confidence interval [CI] 0.03-0.22), in asymptomatic individuals (κ = 0.18, 95% CI 0.02-0.34), and in symptomatic individuals (κ = 0.28, 95% CI 0.17-0.39). The interexaminer reproducibility also was low in all participants (κ = 0.18, 95% CI 0.09-0.27), in asymptomatic individuals (κ = 0.22, 95% CI 0.15-0.37), and in symptomatic individuals (κ = 0.16, 95% CI 0.05-0.27). The standard error of the measurement values were not lower than smallest detectable change values considering a CI of 95% for all participants. CONCLUSION: For this group of asymptomatic and symptomatic participants, the reproducibility of the Downing test was poor. The clinical utility of this test used in isolation is not supported by the present study.
ABSTRACT
Parkinson's disease (PD) involves an initial loss of striatal dopaminergic terminals evolving into a degeneration of dopaminergic neurons in the substantia nigra (SN), which can be modeled by 6-hydroxydopamine (6-OHDA) administration. Since ATP is a danger signal acting through its P2X7 receptors (P2X7R), we now tested if a blood-brain barrier-permeable P2X7R antagonist, Brilliant Blue G (BBG), controlled the 6-OHDA-induced PD-like features in rats. BBG (45 mg/kg) attenuated the 6-OHDA-induced: 1) increase of contralateral rotations in the apomorphine test, an effect mimicked by another P2X7R antagonist A438079 applied intra-cerebroventricularly; 2) short-term memory impairment in the passive avoidance and cued version of the Morris Water maze; 3) reduction of dopamine content in the striatum and SN; 4) microgliosis and astrogliosis in the striatum. To grasp the mechanism of action of BBG, we used in vitro models exploring synaptotoxicity (striatal synaptosomes) and neurotoxicity (dopamine-differentiated neuroblastoma SH-SY5Y cells). P2X7R were present in striatal dopaminergic terminals, and BBG (100 nM) prevented the 6-OHDA-induced synaptosomal dysfunction. P2X7R were also co-localized with tyrosine hydroxylase in SH-SY5Y cells, where BBG (100 nM) attenuated the 6-OHDA-induced neurotoxicity. This suggests that P2X7R contribute to PD pathogenesis through a triple impact on synaptotoxicity, gliosis and neurotoxicity, highlighting the therapeutic potential of P2X7R antagonists in PD.
Subject(s)
Functional Laterality/drug effects , Motor Activity/drug effects , Neurotoxicity Syndromes/drug therapy , Parkinsonian Disorders/drug therapy , Purinergic P2X Receptor Antagonists/therapeutic use , Rosaniline Dyes/therapeutic use , Animals , Avoidance Learning/drug effects , Brain/drug effects , Brain/metabolism , Cell Line, Tumor , Disease Models, Animal , Exploratory Behavior/drug effects , Gliosis/drug therapy , Male , Maze Learning/drug effects , Memory Disorders/drug therapy , Memory Disorders/etiology , Neurotoxicity Syndromes/etiology , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/physiopathology , Purinergic P2X Receptor Antagonists/pharmacology , Rats , Rats, Wistar , Reaction Time/drug effects , Rosaniline Dyes/pharmacologyABSTRACT
The immediate-early gene egr-1 has been shown to have an increased expression during long-term potentiation (LTP). High frequency electrical stimulation induces an increase in such expression in the dorsal horn of the spinal cord. However, evidence demonstrating the activation of this gene in the spinal cord and its relationship with LTP is still scarce. The substance P (SP) has also been associated with LTP in the dorsal horn of the spinal cord following high frequency stimulation. Here we evaluated the expression of both Egr-1 and SP in the sacrolumbar area of the spinal cord after locomotor training in adult rats. Increased neuronal Egr-1 expression was found in the spinal cord sections in rats that underwent locomotor training, especially in laminae IV and X across L3-S4 levels (p<0.05). Conversely, SP expression in synaptic terminals was not altered in the abovementioned regions. Our results suggest that locomotor training activates mechanisms in a similar way to LTP, and is involved in the synaptic plasticity in the spinal cord. The results also indicate that variations in the training protocol influence Egr-1 expression. Such events appear not to be directly influenced by SP, which suggests a plastic process that differs from those triggered by nociceptive stimuli.
