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Vesna Jevtovic-Todorovic

Publications and source records attributed to Vesna Jevtovic-Todorovic.

At least 19 recordsLinked to original sources
PubMed2006

Differential effects of endogenous cysteine analogs on peripheral thermal nociception in intact rats.

Previous in vivo studies indicate that locally injected redox-modulating agents can sensitize polymodal peripheral skin nociceptors resulting in acute changes in pain perception. Since endogenous thiol-modifying redox agents are normally present in the interstitial tissue, and could be found in higher concentration in certain conditions (e.g., tissue injury, inflammation, and ischemia), we designed this study to evaluate the peripheral nociceptive effects of locally injected endogenous-reducing cysteine analogs, L-cysteine, D-cysteine and D,L-homocysteine and endogenous-oxidizing cysteine analogs, L-cystine, D-cystine and D,L-homocystine using the acute model of thermal peripheral nociception in intact rats. We found that the reducing cysteine analogs induced potent dose- and time-dependent hyperalgesia and conversely the oxidizing cysteine analogs induced potent dose- and time-dependent analgesia. In the presence of 3betaOH, a novel neuroactive steroid and potent voltage-dependent blocker of T-type Ca2+ channels, the hyperalgesic effects of the reducing agents were diminished, whereas the analgesic effects of the oxidizing agents were enhanced strongly suggesting that the observed nociceptive effects were, at least in part, mediated via the peripheral T channels. Our findings imply that changes in the redox states of the peripheral nociceptors (favoring either reduced or oxidized forms of cysteine molecules) may function as a local intrinsic mechanism in controlling peripheral pain perception.

Animals↗
PubMed2006

The role of peripheral T-type calcium channels in pain transmission.

Some of the earliest detailed descriptions of biophysical properties of low voltage-activated (LVA) or transient (T) type Ca2+ channels were done using in vitro preparation of primary sensory or dorsal root ganglion (DRG) neurons that are known for their functional role in processing pain signals. However, in spite of these early discoveries, T-type channels were not implicated in sensory transmission in general and pain processing (nociception) in particular until recently. New evidence obtained using an array of techniques such as electrophysiological recordings, pharmacological behavioral experiments as well as molecular techniques strongly supports the role of peripheral T-type Ca2+ channels in boosting nociceptive transmission in a variety of experimental pain models. Therefore, these channels in peripheral sensory neurons may be the important, although previously unappreciated, targets for novel pain therapies. In this article, we review past, present and future findings aimed at illuminating the role of peripheral T-type Ca2+ channels in nociception and the value of these channels as cellular targets for potential drug developments.

Animals↗
PubMed2006

CaV3.2 is the major molecular substrate for redox regulation of T-type Ca2+ channels in the rat and mouse thalamus.

Although T-type Ca(2+) channels in the thalamus play a crucial role in determining neuronal excitability and are involved in sensory processing and pathophysiology of epilepsy, little is known about the molecular mechanisms involved in their regulation. Here, we report that reducing agents, including endogenous sulfur-containing amino acid l-cysteine, selectively enhance native T-type currents in reticular thalamic (nRT) neurons and recombinant Ca(V)3.2 (alpha1H) currents, but not native and recombinant Ca(V)3.1 (alpha1G)- and Ca(V)3.3 (alpha1I)-based currents. Consistent with this data, T-type currents of nRT neurons from transgenic mice lacking Ca(V)3.2 channel expression were not modulated by reducing agents. In contrast, oxidizing agents inhibited all native and recombinant T-type currents non-selectively. Thus, our findings directly demonstrate that Ca(V)3.2 channels are the main molecular substrate for redox regulation of neuronal T-type channels. In addition, because thalamic T-type channels generate low-threshold Ca(2+) spikes that directly correlate with burst firing in these neurons, differential redox regulation of these channels may have an important function in controlling cellular excitability in physiological and pathological conditions and fine-tuning of the flow of sensory information into the central nervous system.

Animals↗
PubMed2006

General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain.

Brain-derived neurotrophic factor (BDNF) is important in supporting neuronal development. BDNF imbalance due to excessive neuronal inhibition can result in the apoptotic degeneration of developing neurons. Since general anesthetics cause profound depression of neuronal activity and are known to induce widespread degeneration in the developing brain, we studied their potential to activate BDNF-mediated developmental neuroapoptosis. When P7 rats (at the peak of brain development) were exposed to a commonly-used and highly pro-apoptotic anesthesia protocol (midazolam, isoflurane, nitrous oxide) for a period of 2, 4 or 6 h, we found that anesthesia modulates the key steps in BDNF-activated apoptotic cascade in two of the most vulnerable brain regions--cerebral cortex and thalamus in time-dependent fashion by activating both Trk-dependent (in thalamus) and Trk-independent p75NTR dependent (in cerebral cortex) neurotrophic pathways. beta-estradiol, a sex hormone that upregulates the protein levels of the activated Akt, protects against anesthesia-induced neuroapoptosis.

Anesthesia, General↗
PubMed2006

The role of T-type calcium channels in peripheral and central pain processing.

It is well established that the voltage-gated calcium (Ca2+) channels can modulate neuronal activity in the peripheral and central nervous system causing a variety of behavioral and neuro-endocrine changes in humans and animals. While much attention was focused on the modulation of high voltage-activated (HVA)-type Ca2+ channels, the role of low voltage-activated (LVA) or transient (T) type Ca2+ channels in sensory processing, and in particular pain processing (nociception) is much less certain. However, recent evidence strongly suggests that modulation of both central and peripheral T-type Ca2+ channels influences somatic and visceral nociceptive inputs and that modulation of T-type Ca2+ currents results in significant alteration of pain threshold in a variety of animal pain models. Therefore, T-type Ca2+ channels in peripheral and central neurons, although previously unrecognized, may be important targets for analgesic therapeutic agents including endogenous compounds. Currently available pain therapies remain insufficient with limited efficacy and numerous side effects. Hence, studies of selective and potent modulators of neuronal T-type Ca2+ channels may greatly aid in revealing roles for these channels in sensory pathways (nociception in particular) and in the development of novel and potentially more effective and safer pain therapies. In the present review, we summarize the putative role of peripheral and central T-type Ca2+ channels in nociception and our recent in vivo and in vitro studies focusing primarily on 5alpha- and 5beta-reduced neuroactive steroids and redox agents that are potent modulators of neuronal T-type Ca2+ channels.

Animals↗
PubMed2005

Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain.

General anesthetics cause widespread apoptotic neurodegeneration in many regions of the developing rat brain. The activation of mitochondria-dependent apoptotic pathway is important in the early stages of anesthesia-induced developmental neuroapoptosis. To investigate potential means of protecting against this type of damage, we studied melatonin, a sleep-promoting agent and antioxidant known to inhibit apoptotic-type neuronal damage by improving mitochondrial homeostasis and stabilizing the inner mitochondrial membrane. When 7-day-old rats (the peak of synaptogenesis) were exposed to a commonly used and highly pro-apoptotic anesthesia cocktail (midazolam, isoflurane, nitrous oxide) in combination with the escalating doses of melatonin (from 1 to 20 mg/kg, s.c.), the severity of anesthesia-induced damage was reduced in a dose-dependent manner in two most vulnerable brain regions--the cerebral cortex and anterior thalamus. Melatonin-induced neuroprotection was mediated, at least in part, via the inhibition of mitochondria-dependent apoptotic pathway since melatonin caused an up-regulation of the anti-apoptotic protein, bcl-X(L), reduction in anesthesia-induced cytochrome c release into the cytoplasm and a decrease in anesthesia-induced activation of caspase-3, an important step in the activation of DNAses and the formation of the apoptotic bodies.

Anesthetics, General↗
PubMed2005

The anesthetics nitrous oxide and ketamine are more neurotoxic to old than to young rat brain.

Nitrous oxide (N2O) and ketamine are common general anesthetics and antagonists of N-methyl-D-aspartate (NMDA) glutamate receptors. In clinically relevant concentrations, they induce a psychotomimetic reaction in humans and pathomorphological changes in the rat brain. We have previously shown that ketamine and N2O in combination cause the neurotoxic reaction in young adult rat brain that is apparently synergistic. Ketamine and N2O are occasionally used in geriatric anesthesia since they do not suppress cardiorespiratory function and thus are beneficial for frail elderly patients. However, in view of the evidence that N2O and ketamine have potentially serious neurotoxic effects, and that they potentiate one another's neurotoxicity, their neurotoxic potential in the aging brain needs to be evaluated. In this study we compared the neurotoxicity of ketamine and N2O, alone or in combination, in aging (18- and 24-month-old) rats and in young adult (6-month-old) rats and found that the aging brain is substantially more sensitive than the young adult brain to the neurotoxic reaction induced by either ketamine alone or the ketamine + N2O combination, but equally sensitive to the neurotoxicity induced by N2O alone.

Aging↗
PubMed2005

New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5alpha-reduced neuroactive steroids.

Neurosteroids are potent blockers of neuronal low-voltage activated (T-type) Ca(2+) channels and potentiators of GABA(A) ligand-gated channels, but their effects in peripheral pain pathways have not been studied previously. To investigate potential analgesic effects and the ion channels involved, we tested the ability of locally injected 5alpha-reduced neurosteroids to modulate peripheral thermal nociception to radiant heat in adult rats in vivo and to modulate GABA(A) and T-type Ca(2+) channels in vitro. The steroid anesthetic alphaxalone (ALPX), the endogenous neurosteroid allopregnanolone (3alpha5alphaP), and a related compound ((3alpha,5alpha,17beta)-3-hydroxyandrostane-17-carbonitrile, (ACN)), induced potent, dose-dependent, enantioselective anti-nociception in vivo and modulation of both T-type Ca(2+) currents and GABA(A)-mediated currents in vitro. Analgesic effects of ALPX were incompletely antagonized by co-injections of the GABA(A) receptor antagonist bicuculline. The neurosteroid analogue ((3alpha,5alpha)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), a compound with GABAergic but not T-type activity, was not analgesic. However, (3beta,5alpha,17beta)-17-hydroxyestrane-3-carbonitrile (ECN)), which has effects on T-type channels but not on GABA(A) receptors, also induced potent enantioselective peripheral anti-nociception. ECN increased pain thresholds less than ALPX, 3alpha5alphaP and ACN. However, when an ineffective dose of CDNC24 was combined with ECN, anti-nociceptive activity was greatly enhanced, and this effect was bicuculline-sensitive. These results strongly suggest that GABA(A) channels do not contribute to baseline pain transmission, but they can enhance anti-nociception mediated by blockade of T-type Ca(2+) channels. In conclusion, we demonstrate that potent peripheral analgesia induced by 5alpha-reduced neurosteroid is mediated in part by effects on T-type Ca(2+) channels. Our results also reveal a role of GABA-gated ion channels in peripheral nociceptive signaling.

Anesthetics↗
PubMed2005

Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain.

Recently, it was reported that anesthetizing infant rats for 6 h with a combination of anesthetic drugs (midazolam, nitrous oxide, isoflurane) caused widespread apoptotic neurodegeneration in the developing brain, followed by lifelong cognitive deficits. It has also been reported that ketamine triggers neuroapoptosis in the infant rat brain if administered repeatedly over a period of 9 h. The question arises whether less extreme exposure to anesthetic drugs can also trigger neuroapoptosis in the developing brain. To address this question we administered ketamine, midazolam or ketamine plus midazolam subcutaneously at various doses to infant mice and evaluated the rate of neuroapoptosis in various brain regions following either saline or these various drug treatments. Each drug was administered as a single one-time injection in a dose range that would be considered subanesthetic, and the brains were evaluated by unbiased stereology methods 5 h following drug treatment. Neuroapoptosis was detected by immunohistochemical staining for activated caspase-3. It was found that either ketamine or midazolam caused a dose-dependent, statistically significant increase in the rate of neuroapoptosis, and the two drugs combined caused a greater increase than either drug alone. The apoptotic nature of the neurodegenerative reaction was confirmed by electron microscopy. We conclude that relatively mild exposure to ketamine, midazolam or a combination of these drugs can trigger apoptotic neurodegeneration in the developing mouse brain.

Animals↗
PubMed2005

Chronic exposure to nitrous oxide increases [3H]MK801 binding in the cerebral cortex, but not in the hippocampus of adult mice.

Chronic exposure of adult mice to inhalational anesthetic nitrous oxide (N2O) results in anesthetic tolerance. N2O is an NMDA (N-methyl-D-aspartate) antagonist. It has been demonstrated that chronic administration of members of the NMDA antagonist class of drugs (e.g., MK801) causes upregulation of NMDA receptors in certain brain regions that could, at least in part, explain the development of tolerance. We sought to determine whether the anesthetic tolerance resulting from chronic exposure to N2O reflects changes in the number and/or distribution of NMDA receptors. We exposed mice to either a 50- or 75-vol% N2O atmosphere continuously for 1 or 2 weeks and performed binding studies with [3H]MK801 and NR1 antibodies. Binding studies revealed a significant (P < 0.05) increase in [3H]MK801 binding in the cerebral cortex after 2 weeks of N2O (50- and 75-vol%) exposure. Immunocytochemical binding of NR1 antibodies in selected brain regions showed no changes in distribution pattern. The timing of this increase in [3H]MK801 binding correlates with the time period required for development of tolerance.

Anesthetics, Inhalation↗
PubMed2004

5beta-reduced neuroactive steroids are novel voltage-dependent blockers of T-type Ca2+ channels in rat sensory neurons in vitro and potent peripheral analgesics in vivo.

T-type Ca(2+) channels are believed to play an important role in pain perception, and anesthetic steroids such as alphaxalone and allopregnanolone, which have a 5alpha-configuration at the steroid A, B ring fusion, are known to inhibit T-type Ca(2+) channels and cause analgesia in a thermal nociceptive model (Soc Neurosci Abstr 29:657.9, 2003). To define further the structure-activity relationships for steroid analgesia, we synthesized and examined a series of 5beta-reduced steroids for their ability to induce thermal antinociception in rats when injected locally into the peripheral receptive fields of the nociceptors and studied their effects on T-type Ca(2+) channel function in vitro. We found that most of the steroids completely blocked T-type Ca(2+) currents in vitro with IC(50) values at a holding potential of -90 mV ranging from 2.8 to 40 microM. T current blockade exhibited mild voltage-dependence, suggesting that 5beta-reduced neuroactive steroids stabilize inactive states of the channel. For the most potent steroids, we found that other voltage-gated currents were not significantly affected at concentrations that produce nearly maximal blockade of T currents. All tested compounds induced dose-dependent analgesia in thermal nociceptive testing; the most potent effect (ED(50), 30 ng/100 microl) obtained with a compound [(3beta,5beta,17beta)-3-hydroxyandrostane-17-carbonitrile] that was also the most effective blocker of T currents. Compared with previously studied 5alpha-reduced steroids, these 5beta-reduced steroids are more efficacious blockers of neuronal T-type Ca(2+) channels and are potentially useful as new experimental reagents for understanding the role of neuronal T-type Ca(2+) channels in peripheral pain pathways.

Analgesics↗
PubMed2004

Mechanical and thermal anti-nociception in rats after systemic administration of verapamil.

Voltage-gated Ca(2+) channels expressed in neurons may contribute to nociceptive information processing. However, the role of L-type Ca(2+) channels in pain transmission is not well understood. In this study, we examined the effects of systemically administered verapamil, an antihypertensive agent and L-type Ca(2+) channel blocker, on mechanical and thermal withdrawal thresholds in rats. Intraperitoneal injections of verapamil induced dose-dependent (3-18 mg/kg) mechanical and thermal anti-nociception in adult rats without altering their sensorimotor abilities. Our data suggest that L-type Ca(2+) channels contribute to acute nociceptive signaling and that anti-nociceptive effects may result from the blockade of these channels.

Analgesics↗
PubMed2004

Redox modulation of peripheral T-type Ca2+ channels in vivo: alteration of nerve injury-induced thermal hyperalgesia.

We reported recently that redox agents, including the endogenous amino acid L-cysteine, modulate T-type Ca2+ currents in primary sensory neurons in vitro, and alter mechanical and thermal nociception in peripheral nociceptors in vivo in intact animals [Neuron 31 (2001) 75]. Here, we studied the effects of locally applied redox agents (L-cysteine and 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) on thermal hyperalgesia in animals with neuropathic pain due to chronic constrictive injury (CCI) of the sciatic nerve. We found that, following injection into the peripheral receptive fields, the endogenous reducing agent L-cysteine increased thermal hyperalgesia in a dose-dependent manner in rats with CCI of the sciatic nerve as well as in sham-operated rats. However, the magnitude of the increase was smaller and duration of effect was shorter in rats with CCI of the sciatic nerve compared to sham-operated animals. DTNB, an exogenous oxidizing agent, induced dose-dependent alleviation of thermal hyperalgesia in rats with CCI of the sciatic nerve and caused analgesia in sham-operated rats. DTNB completely blocked L-cysteine-induced thermal hyperalgesia in both animal groups. Mibefradil, a potent and preferential T-type Ca2+ channel blocker, abolished L-cysteine-induced increase in thermal hyperalgesia in both animal groups suggesting the involvement of T-type Ca2+ channels in peripheral nociception. These results indicate for the first time that redox modulation of T-type Ca2+ channels in rat peripheral nociceptors is operational in pain states caused by peripheral axonal injury. Since thermal hyperalgesia is a common symptom of axonal injury, locally applied oxidizing agents could be used as a novel treatment to ameliorate neuropathic pain.

Animals↗
PubMed2003

Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats.

1. Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. 2. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 microg per 100 microl, respectively. 3. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. 4. Hill slope coefficients for the tested anticonvulsants indicate that the dose-response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. 5. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics.

Acetates↗
PubMed2003

Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.

Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABA(A) receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABA(A) receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.

Anesthetics↗