Influence of anomalous rectifier activation on afterhyperpolarizations of neurons from cat sensorimotor cortex in vitro

1988 ◽  
Vol 59 (2) ◽  
pp. 468-481 ◽  
Author(s):  
P. C. Schwindt ◽  
W. J. Spain ◽  
W. E. Crill
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Sensorimotor Cortex ◽  
Model Parameters ◽  
Fast Decay ◽  
Time Constants ◽  
Anomalous Rectifier ◽  
Betz Cells ◽  
K Currents

1. Large neurons from layer V of cat sensorimotor cortex (Betz cells) were studied to determine the influence of the anomalous rectifier current (IAR) on slow afterhyperpolarizations (AHPs). The neurons were examined using intracellular recording and single-microelectrode voltage clamp in an in vitro brain slice preparation. 2. A faster medium-duration AHP (mAHP) and slower AHP (sAHP) followed repetitive firing (22, 23). The amplitude of the mAHP often increased or remained constant during membrane potential hyperpolarization. The membrane potential trajectory resulting solely from IAR activation was similar to the mAHP. 3. Postrepetitive firing voltage clamp was used to measure directly slowly decaying K+ currents (IK) and IAR at different membrane potentials. IK exhibited both a fast and slow decay. The time constants of the fast decay of IK and IAR activation were similar. IAR increased with hyperpolarization or raised extracellular K+ concentration [( K+]o), whereas both the fast and slow components of IK reversed or nulled near -100 mV and behaved as pure K+ currents in response to raised [K+]o. 4. To determine the precise contribution of IK and IAR to the AHP waveform, theoretical AHPs were computed using a quantitative model based on voltage-clamp measurements. The calculated AHPs were qualitatively similar to measured AHPs. The amplitude of the mAHP showed little change with hyperpolarization because of the increasing dominance of IAR at more negative membrane potentials. The sAHP was little affected by IAR activation. 5. Several model parameters subject to biological variation among Betz cells were varied in the calculations to determine their importance in the AHP waveform. With IK parameters held constant, the amplitude and time course of the mAHP depended on resting potential, membrane time constant, the kinetics of the anomalous rectifier conductance (GAR), and the maximum value of GAR. IAR activation could result in a biphasic AHP even when the fast decay of IK was omitted from the calculations. 6. A wider variation of model parameters revealed behavior that may be relevant to other neurons. Certain values of membrane or IAR activation time constants resulted in a monophasic AHP even when the fast decay of IK was present. The decay of a biphasic AHP could reflect either the onset of IAR or the fast decay of IK, depending on the relative value of their time constants. Procedures are outlined to discriminate between these possibilities using current clamp methods.(ABSTRACT TRUNCATED AT 400 WORDS)

Calcium-dependent potassium currents in neurons from cat sensorimotor cortex

1992 ◽  
Vol 67 (1) ◽  
pp. 216-226 ◽  
Author(s):  
P. C. Schwindt ◽  
W. J. Spain ◽  
W. E. Crill
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Time Constant ◽  
Sensorimotor Cortex ◽  
Pyramidal Neurons ◽  
Outward Current ◽  
Tail Current ◽  
K Current ◽  
The Difference

1. Ca(2+)-dependent K+ currents were studied in large pyramidal neurons (Betz cells) from layer V of cat sensorimotor cortex by use of an in vitro brain slice and single microelectrode voltage clamp. The Ca(2+)-dependent outward current was taken as the difference current obtained before and after blockade of Ca2+ influx. During step depolarizations in the presence of tetrodotoxin (TTX), this current exhibited a fast onset of variable amplitude and a prominent slowly developing component. 2. The Ca(2+)-dependent outward current first appeared when membrane potential was stepped positive to -40 mV. Downsteps from a holding potential of -40 mV revealed little or no time-, voltage-, or Ca(2+)-dependent current. When membrane potential was stepped positive to -40 mV, a prolonged Ca(2+)-dependent outward tail current followed repolarization. The decay of this tail current at -40 mV was best described by a single exponential function having a time constant of 275 +/- 75 (SD) ms. The tail current reversed at 96 +/- 5 mV in 3 mM extracellular K+ concentration ([K+]o) and at more positive potentials when [K+]o was raised, suggesting that it was carried predominantly by K+. 3. The Ca(2+)-dependent K+ current consisted of two pharmacologically separable components. The slowly developing current was insensitive to 1 mM tetraethylammonium (TEA), but a substantial portion was reduced by 100 nM apamin. Most of the remaining current was blocked by the addition of isoproterenol (20-50 microM) or muscarine (10-20 microM). 4. The time courses of the apamin- and transmitter-sensitive components were similar when activated by step depolarizations in voltage clamp, but they were quite different when activated by a train of action potentials. Applying the voltage clamp at the end of a train of 90 spikes (evoked at 100-200 Hz) resulted in an Ca(2+)-dependent K+ current with a prominent rapidly decaying portion (time constant approximately 50 ms at -64 mV) and a smaller slowly decaying portion (time constant approximately 500 ms at -64 mV). The rapidly decaying portion was blocked by apamin (50-200 nM), and the slowly decaying portion was blocked by isoproterenol (20-50 microM). 5. When recorded with microelectrodes containing 2 mM dimethyl-bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (dimethyl-BAPTA), which causes prolonged afterhyperpolarizations, the Ca(2+)-dependent K+ current evoked by step depolarizations had an extremely slow onset and decay. The current recorded after a train of evoked spikes had a similar slow decay.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Membrane Dysfunction Induced by In Vitro Ischemia in Rat Hippocampal CA1 Pyramidal Neurons

1999 ◽  
Vol 81 (4) ◽  
pp. 1872-1880 ◽  
Author(s):  
E. Tanaka ◽  
S. Yamamoto ◽  
H. Inokuchi ◽  
T. Isagai ◽  
H. Higashi
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Pyramidal Neurons ◽  
Membrane Surface ◽  
Bathing Medium ◽  
Ca1 Pyramidal Neurons ◽  
In Vitro Ischemia ◽  
Hippocampal Ca1 ◽  
Electrode Voltage

Membrane dysfunction induced by in vitro ischemia in rat hippocampal CA1 pyramidal neurons. Intracellular and single-electrode voltage-clamp recordings were made to investigate the process of membrane dysfunction induced by superfusion with oxygen and glucose-deprived (ischemia-simulating) medium in hippocampal CA1 pyramidal neurons of rat tissue slices. To assess correlation between potential change and membrane dysfunction, the recorded neurons were stained intracellularly with biocytin. A rapid depolarization was produced ∼6 min after starting superfusion with ischemia-simulating medium. When oxygen and glucose were reintroduced to the bathing medium immediately after generating the rapid depolarization, the membrane did not repolarize but depolarized further, the potential reaching 0 mV ∼5 min after the reintroduction. In single-electrode voltage-clamp recording, a corresponding rapid inward current was observed when the membrane potential was held at −70 mV. After the reintroduction of oxygen and glucose, the current induced by ischemia-simulating medium partially returned to preexposure levels. These results suggest that the membrane depolarization is involved with the membrane dysfunction. The morphological aspects of biocytin-stained neurons during ischemic exposure were not significantly different from control neurons before the rapid depolarization. On the other hand, small blebs were observed on the surface of the neuron within 0.5 min of generating the rapid depolarization, and blebs increased in size after 1 min. After 3 min, neurons became larger and swollen. The long and transverse axes and area of the cross-sectional cell body were increased significantly 1 and 3 min after the rapid depolarization. When Ca2+-free (0 mM) with Co2+ (2.5 mM)-containing medium including oxygen and glucose was applied within 1 min after the rapid depolarization, the membrane potential was restored completely to the preexposure level in the majority of neurons. In these neurons, the long axis was lengthened without any blebs being apparent on the membrane surface. These results suggest that the membrane dysfunction induced by in vitro ischemia may be due to a Ca2+-dependent process that commences ∼1.5 min after and is completed 3 min after the onset of the rapid depolarization. Because small blebs occurred immediately after the rapid depolarization and large blebs appeared 1.5–3 min after, it is likely that the transformation from small to large blebs may result in the observed irreversible membrane dysfunction.

Anomalous rectification in neurons from cat sensorimotor cortex in vitro

1987 ◽  
Vol 57 (5) ◽  
pp. 1555-1576 ◽  
Author(s):  
W. J. Spain ◽  
P. C. Schwindt ◽  
W. E. Crill
Keyword(s):  
Voltage Clamp ◽  
Time Constant ◽  
Sensorimotor Cortex ◽  
Brain Slices ◽  
Resting Potential ◽  
Extracellular Potassium ◽  
Membrane Hyperpolarization ◽  
Anomalous Rectification ◽  
Voltage Dependent

The ionic mechanisms underlying anomalous rectification in large neurons from layer V of cat sensorimotor cortex were studied in an in vitro brain slice. The anomalous rectification was apparent as an increase of slope conductance during membrane hyperpolarization, and the development of anomalous rectification during a hyperpolarizing current pulse was signaled by a depolarizing sag of membrane potential toward resting potential (RP). Voltage-clamp analysis revealed the time- and voltage-dependent inward current (IAR) that produced anomalous rectification. IAR reversal potential (EAR) was estimated to be approximately -50 mV from extrapolation of linear, instantaneous, current-voltage relations. The conductance underlying IAR (GAR) had a sigmoidal steady-state activation characteristic. GAR increased with hyperpolarization from -55 to -105 mV with half-activation at approximately -82 mV. The time course of both GAR and IAR during a voltage step was described by two exponentials. The faster exponential had a time constant (tau F) of approximately 40 ms; the slow time constant (tau S) was approximately 300 ms. Neither tau F nor tau S changed with voltage in the range -60 mV to -110 mV. The fast component constituted approximately 80% of IAR at each potential. Both IAR and GAR increased in raised extracellular potassium [( K+]o) and EAR shifted positive, but the GAR activation curve did not shift along the voltage axis. Solutions containing an impermeable Na+ substitute caused an initial transient decrease in IAR followed by a slower increase of IAR. Brain slices bathed in Na+-substituted solution developed a gradual increase in [K+]o as measured with K+-sensitive microelectrodes. We conclude that GAR is permeable to both Na+ and K+, but the full contribution of Na+ was masked by the slow increase of [K+]o that occurred in Na+ substituted solutions. Chloride did not appear to contribute significantly to IAR since estimates of EAR were similar in neurons impaled with microelectrodes filled with potassium chloride or methylsulfate, whereas, ECl (estimated from reversal of a GABA-induced ionic current) was approximately 30 mV more positive with the KCl-filled microelectrodes. Extracellular Cs+ caused a reversible dose- and voltage-dependent reduction of GAR, whereas intracellular Cs+ was ineffective. The parameters measured during voltage clamp were used to formulate a quantitative empirical model of IAR.(ABSTRACT TRUNCATED AT 400 WORDS)

Properties of persistent sodium conductance and calcium conductance of layer V neurons from cat sensorimotor cortex in vitro

1985 ◽  
Vol 53 (1) ◽  
pp. 153-170 ◽  
Author(s):  
C. E. Stafstrom ◽  
P. C. Schwindt ◽  
M. C. Chubb ◽  
W. E. Crill
Keyword(s):  
Voltage Clamp ◽  
Sensorimotor Cortex ◽  
Potassium Currents ◽  
Spike Threshold ◽  
Sodium Conductance ◽  
Blocking Agents ◽  
Calcium Conductance ◽  
Layer V ◽  
Persistent Sodium Conductance

Properties of the persistent sodium conductance and the calcium conductance of layer V neurons from cat sensorimotor cortex were examined in an in vitro slice preparation by use of a single microelectrode, somatic voltage clamp, current clamp, intra- and extracellular application of blocking agents, and extracellular ion substitution. The persistent sodium current (INaP) attained its steady level within 2-4 ms of a step change in voltage at every potential where it could be examined directly [to about 40 mV positive to resting potential (RP)]. Because of its fast onset INaP can be activated during a single excitatory postsynaptic potential (EPSP) and can influence the subsequent voltage time course and cell excitability. Application of a depolarizing holding potential greater than or equal to 20 mV positive to RP could inactivate spikes, thus allowing examination of INaP at voltages positive to spike threshold. At every potential where INaP was visible, it was mixed with a slow outward current. After depressing potassium currents with blocking agents, INaP could be observed during depolarizations to about 40 mV positive to RP where it is normally hidden by the larger outward currents. Indirect evidence suggests that INaP is present and large during prolonged depolarizations greater than 50 mV positive to RP. INaP was blocked by intracellular injection of the lidocaine derivative QX-314, as well as by extracellular tetrodotoxin (TTX). INaP was much more sensitive to QX-314 than was the height and rate of rise of the spike. This observation and the results in paragraph 3 above are best explained by separate INaP and spike sodium channels. After blockade of INaP and sodium spikes, Ca2+ spikes could be evoked only if potassium currents were first depressed. The Ca2+-dependent nature of the regenerative potentials was indicated by their disappearance when Co2+ or Mn2+ was substituted for Ca2+ in the perfusate and by the appearance of greatly enhanced potentials of similar form when Ba2+ was substituted for Ca2+. Ba2+ substitution greatly enhanced evoked and spontaneous synaptic potentials. Prolonged-plateau action potentials could be evoked in the presence of TTX and Ba2+. Ca2+ spike threshold was 30-40 mV positive to RP, which is significantly more positive than sodium spike threshold. Results of voltage clamp in the normal perfusate and in the presence of Ca2+-blockers or Ba2+ indicated that little or no Ca2+ conductance is activated in the voltage range 25 mV positive to RP where INaP is the dominant ionic current.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Mechanisms of generation of membrane potential resonance in a neuron with multiple resonant ionic currents

2017 ◽  
Author(s):  
David M. Fox ◽  
Hua-an Tseng ◽  
Tomasz G. Smolinski ◽  
Horacio G. Rotstein ◽  
Farzan Nadim
Keyword(s):  
Membrane Potential ◽  
Resonant Frequency ◽  
Ionic Currents ◽  
Calcium Currents ◽  
Neuronal Membrane ◽  
Model Parameters ◽  
Time Constants ◽  
Voltage Range ◽  
Voltage Gated ◽  
Pyloric Network

AbstractNeuronal membrane potential resonance (MPR) is associated with subthreshold and network oscillations. A number of voltage-gated ionic currents can contribute to the generation or amplification of MPR, but how the interaction of these currents with linear currents contributes to MPR is not well understood. We explored this in the pacemaker PD neurons of the crab pyloric network. The PD neuron MPR is sensitive to blockers of H- (IH) and calcium-currents (ICa). We used the impedance profile of the biological PD neuron, measured in voltage clamp, to constrain parameter values of a conductance-based model using a genetic algorithm and obtained many optimal parameter combinations. Unlike most cases of MPR, in these optimal models, the values of resonant- (fres) and phasonant- (fφ=0) frequencies were almost identical. Taking advantage of this fact, we linked the peak phase of ionic currents to their amplitude, in order to provide a mechanistic explanation the dependence of MPR on the ICa gating variable time constants. Additionally, we found that distinct pairwise correlations between ICa parameters contributed to the maintenance of fres and resonance power (QZ). Measurements of the PD neuron MPR at more hyperpolarized voltages resulted in a reduction of fres but no change in QZ. Constraining the optimal models using these data unmasked a positive correlation between the maximal conductances of IH and ICa. Thus, although IH is not necessary for MPR in this neuron type, it contributes indirectly by constraining the parameters of ICa.Author SummaryMany neuron types exhibit membrane potential resonance (MPR) in which the neuron produces the largest response to oscillatory input at some preferred (resonant) frequency and, in many systems, the network frequency is correlated with neuronal MPR. MPR is captured by a peak in the impedance vs. frequency curve (Z-profile), which is shaped by the dynamics of voltage-gated ionic currents. Although neuron types can express variable levels of ionic currents, they may have a stable resonant frequency. We used the PD neuron of the crab pyloric network to understand how MPR emerges from the interplay of the biophysical properties of multiple ionic currents, each capable of generating resonance. We show the contribution of an inactivating current at the resonant frequency in terms of interacting time constants. We measured the Z-profile of the PD neuron and explored possible combinations of model parameters that fit this experimentally measured profile. We found that the Z-profile constrains and defines correlations among parameters associated with ionic currents. Furthermore, the resonant frequency and amplitude are sensitive to different parameter sets and can be preserved by co-varying pairs of parameters along their correlation lines. Furthermore, although a resonant current may be present in a neuron, it may not directly contribute to MPR, but constrain the properties of other currents that generate MPR. Finally, constraining model parameters further to those that modify their MPR properties to changes in voltage range produces maximal conductance correlations.

Slow conductances in neurons from cat sensorimotor cortex in vitro and their role in slow excitability changes

1988 ◽  
Vol 59 (2) ◽  
pp. 450-467 ◽  
Author(s):  
P. C. Schwindt ◽  
W. J. Spain ◽  
R. C. Foehring ◽  
M. C. Chubb ◽  
W. E. Crill
Keyword(s):  
Voltage Clamp ◽  
Sensorimotor Cortex ◽  
Time Course ◽  
Divalent Cations ◽  
Ionic Currents ◽  
Repetitive Firing ◽  
Layer V ◽  
K Concentration

1. The electrophysiological and pharmacological properties of slow afterpotentials in large layer V neurons from cat sensorimotor cortex were studied in an in vitro slice preparation using intracellular recording and single-microelectrode voltage clamp. These properties were used to assess the role of afterpotential mechanisms in prolonged excitability changes. 2. The mean duration of a slow afterhyperpolarization (sAHP) was 13.5 s following 100 spikes evoked at 100 Hz. Its time course was best described by two exponential components, which decayed with time constants of several hundred milliseconds (the early sAHP) and several seconds (the late sAHP). The amplitude of both the early and late components were sensitive to membrane potential and raised extracellular K+ concentration [( K+]o). 3. The early sAHP was reduced when divalent cations were substituted for Ca2+, whereas the late sAHP was unaffected. We conclude that a Ca2+-mediated K+ conductance is responsible for much of the early sAHP. In the presence of tetrodotoxin (TTX), 1-s voltage-clamp steps were used to evoke slow AHPs or outward ionic currents. These AHPs and currents were abolished in Ca2+-free perfusate, but they had a maximum duration of only a few seconds. Thus the slowest outward currents we could observe during voltage clamp in TTX were responsible only for the early sAHP. 4. The possible role of an electrogenic Na+-K+ pump in the late sAHP was examined by applying ouabain to the slice. Ouabain did not reduce selectively the late sAHP, and its effect was best explained by a decrease in intracellular K+ concentration and an increase in [K+]o. 5. Muscarinic and beta-adrenergic agonists reduced or abolished the entire (early and late) sAHP. Neither type of agonist affected the Ca2+-dependent, apamin-sensitive medium-duration afterhyperpolarization (35). We conclude that both the Ca2+-mediated K+ conductance underlying the early sAHP and the Ca2+-independent mechanisms underlying the late sAHP are sensitive to at least two classes of transmitter agonists. 6. We focused on the muscarinic effects. When concentrations greater than 5 microM were employed, the entire (early and late) sAHP was replaced by a slow afterdepolarization (sADP). Muscarine reduced the sAHP directly by reducing the underlying outward ionic currents and indirectly by causing the sADP. The sADP was Ca2+-mediated, since it was abolished by Ca2+-free perfusate but not by TTX. 7. The ionic currents underlying the sAHP and the sADP influenced excitability for seconds following evoked repetitive firing.(ABSTRACT TRUNCATED AT 400 WORDS)

Multiple potassium conductances and their functions in neurons from cat sensorimotor cortex in vitro

1988 ◽  
Vol 59 (2) ◽  
pp. 424-449 ◽  
Author(s):  
P. C. Schwindt ◽  
W. J. Spain ◽  
R. C. Foehring ◽  
C. E. Stafstrom ◽  
M. C. Chubb ◽  
...  
Keyword(s):  
Voltage Clamp ◽  
Sensorimotor Cortex ◽  
Divalent Cations ◽  
Resting Potential ◽  
Equilibrium Potential ◽  
Delayed Rectifier ◽  
Outward Currents ◽  
Potassium Conductances ◽  
The Mean

1. Potassium conductances were studied in large layer V neurons using an in vitro slice preparation of cat sensorimotor cortex. The kinetics and pharmacological sensitivity of K+ currents were studied directly using single microelectrode voltage clamp and indirectly by evoking single or multiple spikes and recording the spike repolarization and subsequent afterhyperpolarizations (AHPs). 2. A fast-decaying afterhyperpolarization (fAHP) and a subsequent medium-duration afterhyperpolarization (mAHP) followed a single spike. The amplitude and duration of the mAHP increased when multiple spikes were evoked at a fast rate (e.g., 100 Hz), and a slower afterhyperpolarization (sAHP) appeared only after sustained repetitive firing. 3. All AHPs were reduced by membrane potential hyperpolarization and raised extracellular K+ concentration, suggesting they were caused by an increased K+ conductance. Only the mAHP and sAHP reversed at the estimated value of potassium equilibrium potential (-100 mV), whereas the mean reversal potential of the fAHP was nearly identical to the mean value of resting potential (-71 mV). 4. Mechanisms underlying spike repolarization, the fAHP, and the mAHP were investigated. Two rapidly activating outward currents, a fast-inactivating current and a slowly inactivating delayed rectifier, were detected by voltage clamp. Both currents were reduced rapidly by tetraethylammonium (TEA). The fast transient current was reduced slowly after divalent cations were substituted for Ca2+ (through a mechanism unrelated to blockade of Ca2+ channels), whereas the delayed rectifier was unaffected. 5. Spike duration was increased and the fAHP was abolished only by blocking agents that reduced the fast outward currents. Effects of extracellular and intracellular TEA were similar. Effects of TEA and Ca2+-free perfusate were additive and resembled the effects of intracellular Cs+. The addition of apamin, d-tubocurare, or Cd2+ was ineffective. We conclude that the two fast outward currents reflect pharmacologically and kinetically separate K+ conductances that are primarily responsible for spike repolarization and the fAHP. 6. Voltage-clamp studies revealed two additional outward currents, which were persistent and Ca2+-mediated. Each current activated and deactivated slowly, but the kinetics of one component were approximately 10 times slower than the other. The decay of these currents gave rise to AHPs resembling the mAHP and the early sAHP. 7. Neither the mAHP nor the sAHP was reduced by TEA. The mAHP was reduced when divalent cations were substituted for Ca2+ or when Cd2+, apamin, or d-tubocurare were added.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Leishmanicidal Activity of Betulin Derivatives in Leishmania amazonensis; Effect on Plasma and Mitochondrial Membrane Potential, and Macrophage Nitric Oxide and Superoxide Production

2021 ◽  
Vol 9 (2) ◽  
pp. 320
Author(s):  
Wilmer Alcazar ◽  
Sami Alakurtti ◽  
Maritza Padrón-Nieves ◽  
Maija Liisa Tuononen ◽  
Noris Rodríguez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Leishmania Amazonensis ◽  
Superoxide Production ◽  
In Vitro Susceptibility ◽  
Intracellular Parasites ◽  
Betulin Derivatives

Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

scholarly journals Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential

2021 ◽  
Vol 7 (2) ◽  
pp. 130
Author(s):  
Nathan P. Wiederhold
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Candida Species ◽  
Mammalian Cells ◽  
Mitochondrial Membrane ◽  
Fungal Infections ◽  
Published Data ◽  
Candida Auris

Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris, as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans, C. glabrata, and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available.

Sign in / Sign up

Export Citation Format

Share Document