ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease

Abstract

Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC). Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. We determined the number of dopaminergic neurons in the substantia nigra, assayed by stereological counting 14 days after the last MPTP injection, the number of Nissl positive neurons in the substantia nigra, and the concentration of catecholamines in the striatum. There was no difference between ASIC1a-deficient mice and wildtype controls. We are therefore not able to confirm that ASIC1a are involved in MPTP toxicity. The difference might relate to the subacute MPTP model we used, which more closely resembles the pathogenesis of Parkinson disease, or to further targets of amiloride.

Fingolimod (FTY720) is not protective in the subacute MPTP mouse model of Parkinson's disease and does not lead to a sustainable increase of brain‐derived neurotrophic factor

“…Tyrosine hydroxylase‐positive (dopaminergic) cells in the lateral SNc of the right hemisphere (see supplemental Figure S1a and S1c) were stereologically counted using the optical fractionator method (StereoInvestigator v11; MicroBrightField, Williston, VT, USA) as described (Komnig et al . ,b). In brief, neurons were manually identified in 50 × 50 μm counting frames presented by the software using an Axio Imager 2 microscope (Carl Zeiss Vision, Göttingen, Germany) and an oil immersion 63x objective (NA 1.4).…”

“…The density of TH‐positive striatal fibres was analysed as previously described (Komnig et al . ,b). In brief, fluorescence 8‐bit images were acquired as z‐stack with five slices 1 μm apart using an 60x oil objective (NA 1.35) and an IX81S1F microscope (Olympus, Hamburg, Germany).…”

“…Catecholamines were measured by HPLC with electrochemical detection as described previously (Komnig et al . ,b). Frozen tissue of left striata was homogenized in 0.1 M perchloric acid (50 μL/mg tissue wet weight) using ceramic beads and a speed mill (max.…”

Inflammasomes in stroke: a triggering role for acid‐sensing ion channels

“…42 Four types of ASICs include ASIC1 (ASIC1a and ASIC1b), ASIC2 (ASIC2a and ASIC2b), ASIC3, and ASIC4; ASIC1a, ASIC2a, and ASIC2b are located in the CNS, cerebral cortex, hippocampus, olfactory bulbs, cerebellum, and amygdala, whereas ASIC3 and ASIC4 are located in the peripheral nervous system. 42 There is evidence suggesting a role for ASICs in the progression of various diseases such as Alzheimer's disease, 43 Parkinson's disease, 44 ischemic stroke, 45,46 migraine, 47 epilepsy, 48 and pain. 49 Studies of Bhowmick et al showed that ASIC1a present in the brain mediates cell death through acidotoxicity in rat hippocampal slices deprived of oxygen.…”

The delta‐opioid receptor and Parkinson’s disease

“…It is well known that 1‐methyl‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP) causes typical PD symptoms in population . The animal experiments and clinical studies show that MPTP is resolved into positive ion MPP + (1‐methyl‐4‐pheny1) after going through the blood‐brain barrier (BBB), and the toxicity is marked by inhibiting the activity of respiratory chain complex phosphoesterase (NADH‐COQ).…”