Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury

Koehn, Liam M.; Noor, Natassya M.; Dong, Qing; Er, Sing-Yan; Rash, Lachlan D.; King, Glenn F.; Dzięgielewska, Katarzyna M.; Saunders, NR; Habgood, Mark D.

doi:10.12688/f1000research.9094.2

Cited by 13 publications

(11 citation statements)

References 70 publications

(106 reference statements)

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“…For example, ASIC2/1a is a dominant subunit expressed in the cortex, and deletion of ASIC2 leads to decreased membrane trafficking of ASIC1a to the cell surface [ 28 ]. Consistent with this idea, both ASIC2 and ASIC1a have been implicated in neuroprotection during disease states [ 29 , 30 , 31 , 32 , 33 , 34 ]. ASIC2 has also been implicated in baroreceptor activities related to the cardiovascular system [ 35 ].…”

Section: Introductionmentioning

confidence: 76%

Acid-Sensing Ion Channels and Mechanosensation

Ruan

Tribble

Peterson

et al. 2021

IJMS

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Acid-sensing ion channels (ASICs) are mainly proton-gated cation channels that are activated by pH drops and nonproton ligands. They are part of the degenerin/epithelial sodium channel superfamily due to their sodium permeability. Predominantly expressed in the central nervous system, ASICs are involved in synaptic plasticity, learning/memory, and fear conditioning. These channels have also been implicated in multiple disease conditions, including ischemic brain injury, multiple sclerosis, Alzheimer’s disease, and drug addiction. Recent research has illustrated the involvement of ASICs in mechanosensation. Mechanosensation is a form of signal transduction in which mechanical forces are converted into neuronal signals. Specific mechanosensitive functions have been elucidated in functional ASIC1a, ASIC1b, ASIC2a, and ASIC3. The implications of mechanosensation in ASICs indicate their subsequent involvement in functions such as maintaining blood pressure, modulating the gastrointestinal function, and bladder micturition, and contributing to nociception. The underlying mechanism of ASIC mechanosensation is the tether-gate model, which uses a gating-spring mechanism to activate ASIC responses. Further understanding of the mechanism of ASICs will help in treatments for ASIC-related pathologies. Along with the well-known chemosensitive functions of ASICs, emerging evidence has revealed that mechanosensitive functions of ASICs are important for maintaining homeostasis and contribute to various disease conditions.

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Section: Introductionmentioning

confidence: 76%

Acid-Sensing Ion Channels and Mechanosensation

Ruan

Tribble

Peterson

et al. 2021

IJMS

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“…Statistical differences between concentration ratios were determined using Kruskal-Wallis tests with Dunn's correction for multiple comparisons. Least squares linear regression with analysis of covariance was conducted as previously described [31]. Significance levels were set at p < 0.05.…”

Section: Statisticsmentioning

confidence: 99%

Transfer of rhodamine-123 into the brain and cerebrospinal fluid of fetal, neonatal and adult rats

Koehn

Dzięgielewska

Habgood

et al. 2021

Fluids Barriers CNS

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Background Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages it must bypass efflux transporters at both the placental barrier and brain barriers themselves. Following birth, placental protection is no longer present and brain barriers remain the major line of defense. Understanding developmental differences that exist in the transfer of PGP substrates into the brain is important for ensuring that medication regimes are safe and appropriate for all patients. Methods In the present study PGP substrate rhodamine-123 (R123) was injected intraperitoneally into E19 dams, postnatal (P4, P14) and adult rats. Naturally fluorescent properties of R123 were utilized to measure its concentration in blood-plasma, CSF and brain by spectrofluorimetry (Clariostar). Statistical differences in R123 transfer (concentration ratios between tissue and plasma ratios) were determined using Kruskal-Wallis tests with Dunn’s corrections. Results Following maternal injection the transfer of R123 across the E19 placenta from maternal blood to fetal blood was around 20 %. Of the R123 that reached fetal circulation 43 % transferred into brain and 38 % into CSF. The transfer of R123 from blood to brain and CSF was lower in postnatal pups and decreased with age (brain: 43 % at P4, 22 % at P14 and 9 % in adults; CSF: 8 % at P4, 8 % at P14 and 1 % in adults). Transfer from maternal blood across placental and brain barriers into fetal brain was approximately 9 %, similar to the transfer across adult blood-brain barriers (also 9 %). Following birth when placental protection was no longer present, transfer of R123 from blood into the newborn brain was significantly higher than into adult brain (3 fold, p < 0.05). Conclusions Administration of a PGP substrate to infant rats resulted in a higher transfer into the brain than equivalent doses at later stages of life or equivalent maternal doses during gestation. Toxicological testing of PGP substrate drugs should consider the possibility of these patient specific differences in safety analysis.

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“…Statistical differences between concentration ratios were determined using Kruskal-Wallis tests with Dunn's correction for multiple comparisons. Least squares linear regression with analysis of covariance was conducted as previously described (30). Significance levels were set at p<0.05.…”

Section: Statisticsmentioning

confidence: 99%

Transfer of Rhodamine-123 into the Brain and Cerebrospinal Fluid of Fetal, Neonatal and Adult Rats

Koehn

Dzięgielewska

Habgood

et al. 2020

Preprint

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Background: Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages it must bypass efflux transporters at both the placental barrier and brain barriers themselves. Following birth, placental protection is no longer present and brain barriers remain the major line of defense. Understanding developmental differences that exist in the transfer of PGP substrates into the brain is important for ensuring that medication regimes are safe and appropriate for all patients. Methods: In the present study PGP substrate rhodamine-123 (R123) was injected intraperitoneally into E19 dams, postnatal (P4, P14) and adult rats. Naturally fluorescent properties of R123 were utilized to measure its concentration in blood-plasma, CSF and brain by spectrofluorimetry (Clariostar). Statistical differences in R123 transfer (ratios between tissue and plasma concentrations) were determined using Kruskal-Wallis tests with Dunn’s corrections. Results: Following maternal injection the transfer of R123 across the E19 placenta from maternal blood to fetal blood was around 20%. Of the R123 that reached fetal circulation 41% transferred into brain and 38% into CSF. The transfer of R123 from blood to brain and CSF was lower in postnatal pups and decreased with age (brain: 43% at P4, 22% at P14 and 9% in adults; CSF: 8% at P4, 8% at P14 and 1% in adults). Transfer from maternal blood across placental and brain barriers into fetal brain was approximately 8%, similar to the transfer across adult blood-brain barriers (9%). Following birth when placental protection was no longer present, transfer of R123 from blood into the newborn brain was significantly higher than into adult brain (3 fold, p<0.05). Conclusions: Administration of a PGP substrate to infant rats resulted in a higher transfer into the brain than equivalent doses at later stages of life or equivalent maternal doses during gestation. Toxicological testing of PGP substrate drugs should consider the possibility of these patient specific differences in safety analysis. Trial Registration: N/A.

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Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury

Cited by 13 publications

References 70 publications

Acid-Sensing Ion Channels and Mechanosensation

Acid-Sensing Ion Channels and Mechanosensation

Transfer of rhodamine-123 into the brain and cerebrospinal fluid of fetal, neonatal and adult rats

Transfer of Rhodamine-123 into the Brain and Cerebrospinal Fluid of Fetal, Neonatal and Adult Rats

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