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To date, it is known that short-term episodes of a
moderate hypoxia (hypoxic preconditioning) can improve the tolerance to severe
hypoxia or ischemia. In the problem of hypoxic preconditioning, the brain is
central as the most sensitive organ to hypoxia and as the coordinator of the
functions of all body organs and systems. Fundamental importance in the study
of nervous tissue has the functional specificity and individual sensitivity to
hypoxia of separate neuronal populations and the corresponding brain structures.
On the model of single moderate hypobaric hypoxia in rats, using preparative
technique and biochemical methods for determining the marker of cholinergic
system of choline acetyltransferase in the sub-synaptic fractions of brain
structures and also the influences of nicotinic antagonists on the
preconditioning, we found: 1) the efficiency of hypoxic preconditioning does
not depend on an innate resistance to severe hypoxia and prior severe hypoxic
experience of rats; 2) the hypoxic preconditioning eliminates the differences
in resistance to hypoxia between the groups of rats with different innate
resistance to severe hypoxia and intact rats and 3) in the rats with different
prior hypoxic experiences, the same preconditioning effect is achieved by different
cholinergic pathways. The variety of neuronal pathways to achieve the same
physiological affect demonstrates a great adaptive potential of brain. We have
tried to identify some cholinergic neuronal populations or areas of their
actions which may be involved in the hypoxic preconditioning mechanisms. The
specific mechanisms of preconditioning may be the promising therapeutic
targets. At the same time, for the study of innate mechanisms in intact rats,
it is necessary to look for criteria for separation of animals in their
sensitivity to hypoxic preconditioning. One such criterion (prepulse
inhibition) is presented in this review.
Keywords: Severe
hypoxia, Apne, Hypoxic preconditioning, Caudal brainstem, Cortex, Neuronal
networks, Cholinergic system, Synaptic choline acetyltransferase, Alpha7 and
non-alpha7 nicotinic receptors, Methyllycaconitine, Mecamylamine
Abbreviations: ACh:
Acetylcholine; C1: Area of Premotor Sympathetic Neurons; ChAT: Choline
Acetyltransferase; DFA: Dorsal Facial Area; HBH: Moderate Hypobaric Hypoxia;
LDT: The Laterodorsal Tegmental Nucleus; mAChRs: muscarinic Cholinergic
Receptors; MCVA: Medullary Cerebral Vasodilator Area; MEC: Mecamylamine; MLA:
Methyllycaconitine; nAChRs: nicotinic Cholinergic Receptors; NTS: The Nucleus
Tractus Solitary; PPI: prepulse inhibition of the acoustic startle reaction;
PPT: the pedunculopontine tegmental nucleus; SHBH: severe Hypobaric Hypoxia; T:
Survival Time under SHBH Conditions; VLM: The Ventrolateral Medulla
INTRODUCTION
The relevance of hypoxic preconditioning is
due to its ability to increase the body's resistance to hypoxic/ischemic
stress. Moreover, hypoxic component forms the pathogenesis of many diseases and
an understanding of the preconditioning mechanisms is a high priority [1-7].
Special
importance in the study of brain functions is to identify the functional neural
networks [8-11]. In the hypoxic adaptation, the key role belongs to the
autonomic respiratory and cardiovascular systems. Their central represendation
is located in the medulla oblongata and pons varolii (caudal brainstem) and
closely interrelate with the “respiratory centre”, groups of respiratory
neurons, which support respiratory rhythm [12-16]. The neuronal networks of
central regulation of breathing and blood circulation in health and disease are
in the focus of many researchers because of the basic value of this knowledge
to maintain the
Data on the topography, functional significance and interaction of the
central components of the autonomic cardiorespiratory system responsible for
respiration are most fully presented in the review [14]. We have laid the
remarkably laconic and optimal abstract of these authors as a basis for a
summary of the anatomic basis of the center control of respiration.
Cardiorespiratory activity is controlled by a networks of neurons located
within the lower brainstem (the caudal brainstem in our paper). The basic
rhythm of breathing is generated by neuronal circuits within the medullary pre-Bötzinger
complex (preBötC), modulated by pontine and other inputs from cell groups
within the medulla oblongata and then transmitted to bulbospinal pre-motor
(reticulospinal) neurons neurons of area C1 of the rostral ventrolateral
medulla (VLM) that relay the respiratory pattern to cranial and spinal motor
neurons controlling respiratory muscles. Cardiovascular sympathetic and vagal
activities have characteristic discharges that are patterned by respiratory
activity. This patterning ensures ventilation-perfusion matching for optimal
respiratory gas exchange within the lungs. Peripheral arterial chemoreceptors
and central respiratory chemoreceptors are crucial for the maintenance of
cardiorespiratory homeostasis. Inputs from these receptors ensure adaptive changes
in the respiratory and cardiovascular motor outputs in various environmental
and physiological conditions. Many of the connections in the reflex pathway
that mediates the peripheral arterial chemoreceptor input network they have
been established. The nucleus tractus solitarii (NTS), the respiratory network
of VLM, pre-sympathetic circuitry and vagal pre-ganglionic neurons at the level
of the medulla oblongata are integral components, although supramedullary
structures also play a role in patterning autonomic outflows according to
behavioral requirements.
This consensus should be supplemented with studies that the authors did
not include in the review, or appeared later, about the neuronal components of
the circuitry, especially significant for the maintenance of cardiorespiratory
homeostasis under hypoxia and/or hypercapnia conditions: 1) the two centres and
their outputs were identified for redistribution of blood flow towards the
brain, dorsal facial area (DFA) [18] and medullary cerebral vasodilator area
(MCVA) [19]; 2) new data has been obtained on functional features of the center
of active expiratory, the pontine parafacial respiratory group (pFRG) of
non-chemosensitive to CO2 neurons and chemosensitive to CO2
and H+ distinct populations of neurons in the the retrotrapezoid
nucleus [20-25], and 3) some details of pFRG complex links with preBötC have
been revealed [21,24], which led to the further development of physiological
mechanisms within the cardiorespiratory
circuitry. There is a concept of ‘distributed’ chemosensitivity that has been
observed throughout the caudal brainstem [14], which is confirmed by the new
data.
The stimulation of respiration, heart activity and blood circulation and
redistribution of blood flow towards the brain, lungs and heart is the primary
and immediate compensatory response to an environmental hypoxia that is always
recorded in the autonomic respiratory and cardiovascular networks [26-30]. In
general, this systemic response is a result of the wide cooperation of different
functional groups of neurons of the caudal brainstem mentioned above. Under
severe environmental hypoxia incompatible with survival, an initial
augmentation of respiratory activity followed by secondary depression, which
leads to central apnea, i.e., inactivation of the inspiratory muscles as a
result of disturbances of the central respiratory rhythm (cat, rat) [29-31].
From the ‘distributed’ concept, the control mechanisms of chemosensory
and respiratory neurons at different locations may be distinct. This applies
equally to the norm and to the pathology and implies a multiplicity of central
apnea mechanisms. The assumption is supported by data that, under conditions of
severe hypobaric hypoxia (3% O2), animals within the same species
(cat, rat), despite the similar dynamics of the systemic reaction, clearly
differ in the expressivity of reaction at its different stages and this is
consistent with animal resistance to hypoxia (an exposure time of hypoxia
before apnea): according to hemodynamic and respiratory indicators, the
initial, compensatory stage of the systemic response is more pronounced in the
more resistant to hypoxia individuals, and, conversely, the stage of depression
is most pronounced in the least resistant individuals [29,30].
Under moderate hypoxia, the all compensatory reactions are maintained
during the whole session of hypoxic training in cats or rats [28,30] and any of
them can be the physiological basis of adaptation. Our interest lays in the
study of the neurotransmitter synaptic mechanisms of hypoxic preconditioning in
order to identify the neuronal populations involved in the adaptive respiratory
partways. The neurotransmitter pattern of local central respiratory networks of
the cardiorespiratory system is far from complete. At the same time, data on
the neurotransmitter specificity of neurons and their effects in the central
regulation of respiration are accumulated. This allowed us to analyze the value
of some neoritransmitter systems (opioid, serotoninergic, GABAergic, glycinergic
and adenosinergic) at the level of the caudal brain stem in the mechanisms of
apnea [32]. The cholinergic contribution in the mechanisms of apnea and
possible ways to prevent it were carefully analyzed in another article [33] and
here we provide a mini-review of this publication.
Starting from Loeschcke studies [34,35], the central effects of
acetylcholine (ACh) and its analogues on the respiration and blood circulation
are intensively investigated. Cholinergic participation is detected in the
majority of the functional sites of cardiorespiratory networks, as well as the
ambiguity of the cholinergic effects depending on drug application site,
reception and dose. However, there were no data on the participation of
cholinergic system in the cardiorespiratory networks under hypoxic
preconditioning.
At the same time, it was shown in various organs including the brain that
ACh simulates the effects of ischaemic/hypoxic preconditioning usually through
nicotinic receptors (nAChRs) [35,37]. Homomeric alpha7 and heteromeric
alpha4beta2, alpha3beta4 and alpha3beta2 are the most widespread nAChR subtypes
in the mammalian brain [38] and they are expressed at all levels of autonomic
regulation of respiration and blood circulation [33].
The most unstable to ischaemic/hypoxic impacs are the structures of
forebrain [39], among which the cortex and hippocampus are of greatest interest
as the higher brain structures responsible for cognitive functions. Both the
cortex and hippocampus interact with the cardiorespiratory systems,
participating in the regulation of voluntary breathing and supposedly adaptive
reactions of the cardiovascular and respiratory systems [8-11,13,16].
In our investigations, single moderate hypobaric hypoxia (HBH) had a
marked hypoxic preconditioning effect on rats, increasing a resistance to
severe hypobaric hypoxia (SHBH) in intact rats and high- and low-resistant,
pre-tested to SHBH rats [33,40]. Our data confirmed the obligatory
participation of the brainstem autonomic systems in the HBH precondition
mechanisms. The cholinergic synaptic pool of the caudal brainstem reacted to
HBH in all groups of rats unlike those of the cortex and no reaction was shown
in the hippocampus (biochemical data) [33,41].
Also, we found that, on the one hand, HBH equalized the resistance to
SHBH in all rat groups [33, 40] and on the other hand, the same preconditioning
effect was achieved by different synaptic plastic tools in different
populations of pre-synapses [33,41]. It assumed the involvement of different
neuronal networks in the preconditioning mechanisms in this rat groups.
The assumption was supported by our pharmacological data. We got the
effects on HBH of antagonists of alpha7 and non-alpha7 subtypes of the
nicotinic receptors (nAChRs) methyllycaconitine (MLA) and mecamylamine (MEC) in
the low-resistent rat group and did not receive any effects in the
high-resistent and intact rat groups. Moreover, in the low-resistent rat group,
the effects of both antagonists on HBH were radically different from their
direct effects on innate resistance to SHBH [33].
Thereby, HBH preconditioning is realized by the own mechanisms which
eliminate the differences in innate resistance to SHBH between groups of rats
independently of their prior hypoxic experiences.
Using the literature and own data, we have tried to identify some
cholinergic neuronal populations or areas of their actions which may be
involved in the hypoxic preconditioning mechanisms to delay the time of apnea.
METHODICAL
APPROACHES
Briefly, our experimental approaches on the study of cholinergic neuronal
mechanisms of hypoxic preconditioning. For the details of experimental
procedures [33,42].
Animals
The male outbred albino rats aged 2-2.5 months (200-250 g) at the
beginning of the studies. All animal care and experimental procedures were
conducted in accordance with the official regulations of the European
Communities Council Directive on the use of laboratory animals of 24 November
1986 (86/609/EEC).
Hypoxic
models
Hypoxic preconditioning, the continuous hypobaric hypoxia (HBH) at
altitude of 5000 m (11% O2), 60 min. Test for resistance to hypoxia,
severe hypobaric hypoxia (SHBH) at critical altitude of 11500 m (4.5% O2).
In the latter case, resistance to hypoxia was recorded with respect to time (T)
until agonal inspiration (apnea).
Preparative
methods for biochemical investigations
From each brain structure (caudal brainstem, cortex and hippocampus), the
sub-fractions of synaptoplasm and synaptic membranes were isolated from the
fractions of “light” and “heavy” synaptosomes by routine preparative methods
using discontinuous sucrose gradients.
Analytical
methods
In the sub-synaptic fractions, the choline acetyltransferase activity
(ChAT, EC 2.3.1.6, functional marker of cholinergic neurons) by radiometric
method Fonnum and protein content by spectrophotometric method Lowry were
assayed.
The sub-synaptic level of fractionation made it possible to study the
water-soluble and membrane-bound indicators of two major functionally different
pre-synaptic compartments and to disclose a response to exposure of the
membrane-bound ChAT, whose activity is significantly less to that of the
water-soluble ChAT [41,43,44].
Drug
application
The rats received a single intraperitoneal injection of
methyllycaconitine citrate (MLA, Tocris), a selective antagonist of alpha7
subtype of nAChRs, or mecamylamine hydrochloride (MEC, Sigma), a selective
antagonist of non-alpha7 subtypes of nAChRs. Respectively, MLA (1.4 nmol/kg) or
MEC (3.9 nmol/kg) was injected immediately (for MLA) or 30 min (for MEC) before
SHBH or HBH. The control to drugs rat groups received physiological saline.
Statistics
The data were calculated using the non-parametric one-sided Fisher’s
Exact Test and the r-criterion of the Pearson’s correlative test.
EXPERIMENTAL
PROTOCOLS
In each lot of rats 4-5 weeks before the experiments, part of the animals
were pre-tested under SHBH and divided into groups of high- and low-resistance
to hypoxia with T1>7 min and T1<3.5 min, respectively. Then the rats in
each pre-tested group and rats in not pre-tested group (intact rat group) were
subdivided into experimental (HBH-SHBH) and control (SHBH) subgroups. The rats
of each experimental group were subjected to the HBH session and, four min
after the end of training, they were subjected to SHBH or taken in the
biochemical experiment. The control groups underwent all procedures except for
HBH simultaneously with the corresponding experimental groups.
In pharmacological experiments in each rat group, animals in the HBH-SHBH
as well as in SHBH subgroup were subdivided into the drug (experimental) and
saline (control) subgroups. After injection of MLA or MEC in the drug subgroups
and saline in the control subgroups, animals were subjected to SHBH or to
HBH-SHBH as described above.
IDENTIFICATION
OF CHOLINERGIC NEURONAL POPULATIONS AND PARTWAYS OF CAUDAL BRAINSTEM AND CORTEX
INVOLVED IN THE HBH PRECONDITIONING MECHANISMS AND/OR TARGETS OF THEIR SYNAPTIC
ACTION
So, HBH removes the direct effects of SHBH. After HBH sessions, all rats
in the HBH-SHBH groups show a similar range for resistance to SHBH with mean T
values of 14.7 ± 1.7, 14.9 ± 1.7 and 13.2 ± 1.8 min vs. mean T values under
direct SHBH exposure 5.2 ± 0.9, 10.3 ± 2.2 and 2.6 ± 0.5 min in the intact,
high- and low-resistant rat groups, respectively. The T values of all groups
formed the same variational series with the resistance to SHBH over a wide
range from 4.5 to 24.5 min.
In accordance with the biochemical experiments, the reaction on HBH of
synaptic pool of caudal brainstem and cortex in the studied groups of rats were
found and no reaction was shown in the hippocampus. This was the basic
experimental material for the identification of neuronal cholinergic pathways
of hypoxic preconditioning. Additional material for analysis gave our pharmacological
data [33,41].
Briefly, it was revealed the following.
Sources
of cholinergic influences in the caudal brainstem and cortex
According to immunocytochemical data, the caudal brainstem includes
several cholinergic sources: 1) projections from the reticular formation of the
midbrain tegmentum; 2) afferents of the nodose ganglion sensory neurons from
the lung mechanoreceptors to NTS; and 3) neurons of the pons varolii and
medulla oblongata, including neurons of reticular areas, NTS, and efferent
parasympathetic preganglionic neurons of the motor cranial nerves nuclei.
The cortex (and hippocampus) has two main cholinergic sources, namely: a
major source is the cholinergic projection neurons from the basal forebrain
nuclei, and minor source, the cholinergic interneurons. We previously showed
for the cortex and hippocampus that pre-synapses of the cholinergic projection
neurons from the basal forebrain nuclei are mainly concentrated in the light
synaptosomal fractions and pre-synapses of the cholinergic interneurons in the
heavy synaptosomal fractions [44].
Low-resistant
rats
In the caudal brainstem, the inhibition of water-soluble ChAT activity by
17% (p<0,025) in the pre-synapses of heavy synaptosomal fraction was found
in the HBH-SHBH subgroup. Conversely, from our previous study, in the fraction
of heavy synaptosomes, isolated from NTS, pronounced activation of ChAT (represented
mainly by water-soluble ChAT activity) was observed at the time of apnea under
SHBH in the low-resistant rats [43]. Taken together, it seems that the reaction
of the cholinergic subtype of lung barosensitive C-fibres conducting
afferentation to NTS through the nodose ganglion was observed in this rat group
[45,46]. The apnea is often preceded by the classic reflex of C-fibres
(frequent shallow breathing, bradycardia and hypotension) [46-48]. The
weakening of their influences under HBH led to the suppression of
parasympathetic reflexes occurring in NTS and thereby to the augmentation of
resistance to SHBH.
In our study, both nAChRs antagonisns MLA and MEC potentiated the innate
resistance to severe hypoxia: the T values in both SHBH drug subgroups were
significantly higher compared to corresponding control SHBH subgroups (almost
twice for MLA, p<0.025 and more than three times for MEC, p<0.05). In the
HBH-SHBH drug subgroups, MLA only but not MEC had an influence on resistance to
SHBH after HBH exposure and in this case MLA twice narrowed the preconditioning
effect of HBH (p<0.025).
Given the reaction of the cholinergic pool only in the caudal brainstem
in the low-resistant rats, as well as the low doses of both antagonists
providing their central effect [49], we assumed that the antagonists also act
within the caudal brainstem region and that their direct action on the innate
resistance to hypoxia in the SHBH drug subgroups of rats occurs specifically
within the NTS. According to the literature data in NTS, the nAChRs, including
alpha7subtype, alpha3 and alpha4 subunits, are involved in parasympathetic
functions only [49-54]. Therefore, MLA and MEC initiated the suppression of
parasympathetic reflexes occurring in NTS and thereby increased their
resistance to SHBH in the SHBH drug subgroups.
In the same time, the cholinergic C-fibres could act on the same nAChRs
as our antagonists directly and indirectly affecting theirs through secondary
cholinergic barosensitive neurons [50,52,54-56]. In this way, the effects of
MLA and MEC, potentiating resistance to SHBH, could not appear after HBH,
against the background of the reduced cholinergic C-fibres influences. In other
words, HBH preacted the protective effect of both antagonists.
Based on the above, it can be suggested that the suppression of resistance
to hypoxia of the low-resistant rats under HBH by MLA took place in brainstem
areas outside NTS, in which preconditioning effects could be stimulated through
alpha7 nAChRs. That site may be 1) sympathoexcitatory pressor zone C1 in the
rostral VLM [49,57] and it is assumed that the main way for cholinergic
transmission is volume (non-synaptic) in this zone [58,59]; 2) DFA [60] and,
possibly, the motoneurons in the hypoglossal nucleus [61,62].
High-resistant
rats
In this rat group, HBH provoked inhibition of the water-soluble ChAT
activity by 19% (p<0.05) in the pre-synapses of light synaptosomal fraction
of the caudal brainstem and membrane-bound ChAT by 33% (p<0.025) in
pre-synapses of cortical projection neurons (the cortical light synaptosomal sub-fraction).
These HBH-induced changes in ChAT activity correlated with each other
(r=+0.911, p<0.02). In the high-resistant rats, there were no changes in the
ChAT activity at the time of apnea under SHBH in the light and heavy fractions
of synaptosomes, isolated from NTS [43]. From these data, it was necessary to
seek either a direct connection between the cholinergic neurons of the caudal
brainstem outside NTS and cortical projection neurons, or cholinergic neurons
that connect the caudal brainstem and cortical projection neurons.
According to the literature, the second variant was validated. The
tegmental nuclei of middle brain, including
the laterodorsal (LDT) and/or pedunculopontine (PPT) nuclei, are the
major switch between the caudal brainstem formations and basal forebrain nuclei
and other higher brain structures [11,63,64]. Cholinergic neurons of LDT and
PPT send plurality of the fibres to both the pons and medulla oblongata [59,63,65]
and also to the cortical cholinergic projection neurons of the basal forebrain
nuclei [63,65] and it is important that some of them send the projections in
both directions [65].
Neurons of the PPT and LDT nuclei are projected into the many regions of
caudal brainstem [59,65]. We did not have any influence of the antagonists of
nAChRs on HBH-induced preconditioning in the high-resistant group of rats.
Thus, we searched the sites of caudal brainstem, in which decrease of the
cholinergic effects through muscarinic cholinergic receptors (mAChRs) would
contribute to the hypoxic preconditioning to delay the time of apnea.
We identified two such targets of the PPT and LDTprojections: 1) the
motoneurons of upper airway from the hypoglossal 12th cranial nerve nucleus
that are pre-synaptically inhibited by the M2 subtype of mAChRs stimulation
[66] and 2) the laryngeal motoneurons of the upper airway located in the loose
formation of the nucleus ambiguous in the rostral VLM, the majority of which
through the mAChRs stimulate the constriction of intrinsic laryngeal muscles
conjugated with expiration [67,68].
Intact
rats
In the intact rat group, in the caudal brainstem, HBH provoked an
interconnected increase in the water-soluble ChAT activity and protein content
by 27% (p<0.025) and 22% (p>0.05), respectively, in the light
synaptosomal fraction (r=+0.928, p<0.02) and decreased in the membrane-bound
ChAT activity and protein content by 33% and 16% (p<0.025), respectively, in
the heavy fraction (r=+0.933, p<0.02). The diminution of values of both
indicators in the heavy fraction was inversely proportional to their growth in
the light fraction (for ChAT activity, r=–0.962, p<0.02; for protein
content, r=–0.921, p<0.05) and we believe that HBH initiated the transformation
of cholinergic pre-synapses from the heavy fraction of synaptosomes which
altered their density characteristics and during gradient fractionation the
transformed presynaptic population appeared in the light fraction. Moreover,
the water-soluble ChAT was activated in the transformed presynapses [41].
Several respiratory-related sites exist in VLM in which ACh stimulated
breathing, maintained an inspiration through mAChRs and/or nAChRs [19,22,56].
Also, innervation of DFA by nicotine initiated the elevation of cerebral blood
flow [60]. However, as in the group of the high-resistant rats, there was no
effect of the nAChR antagonists for resistance to hypoxia and any information
to identify the populations of cholinergic neurons of the caudal brainstem,
involved in the hypoxic preconditioning mechanisms in the intact rats.
The water-soluble ChAT was activated by 28% (p<0.05) in the cortical
interneurons (the heavy fraction of synaptosomes). There was no correlation
between the ChAT activity in the cortex and caudal brainstem in this rat group
because of the absence of a direct link between the brain stem neurons and
cortical cholinergic interneurons. The activation of ACh synthesis under HBH in
the cortical interneurons could be related to their function of redistribution
of the blood flow towards the brain. With respect to cerebral vessels, direct
contacts with small cortical vessels and vasodilator effects of both the
cholinergic projective neurons and interneurons were detected [69,70]. Thereby
in intact brain, the cortical cholinergic interneurons might be involved in the
local mechanisms to maintain of cerebral blood flow.
CONCLUSION
Neuronal, mediator and receptor mechanisms of hypoxic preconditioning are
poorly understood to date. The variety of neuronal pathways to achieve the same
physiological affect demonstrates a great adaptive potential of brain.
However, the intact rats had a synaptic response to HBH, the opposite of
that of pre-tested rats: the activation of cardiorespiratory functions
dominated in the intact rats, while the inhibition of pathways initiating apnea
appeared in the pre-tested rats. Evidently, that the single pre-testing under
SHBH altered synaptic and neuronal preconditioning mechanisms [33,40].
Nonetheless, the specific preconditioning mechanisms of the pre-testing rats
may be the therapeutic targets for individuals who survived severe hypoxia.
Cholinergic response, revealed in the caudal brainstem of the intact
rats, did not provide any help for the identification of neuronal population
reacted to HBH. At the same time, the wide range of HBH-initiated resistance to
SHBH and some other evidence [40] convince us that reaction to HBH in the
intact rats can be based on different preconditioning mechanisms. Also possible
that the multiplicity of mechanisms in the regulation of vital functions such
as breathing and blood circulation must be inherent to every organism as the
ability to make a quick choice to maintain its viability. This is evidenced by
the concept of ‘distributed’ chemosensitivity that provides ‘the necessary
level of redundancy within the system’ [14].
To identify the innate preconditioning mechanisms, it is necessary to
look for criteria for separation of animals in their sensitivity to adaptive
hypoxia. One such criterion has recently been found. It was a prepulse
inhibition (PPI) estimated in the model of acoustic startle reaction. It was
found a correspondence between the values of PPI and T initiated by HBH
[32,71]. There was no correlation between PPI and innate SHBH resistance [71]
and between PPI and resistance initiated by HBH in the pre-testing to SHBH rats
(unpublished data). So, the PPI model can be used to predict the innate
efficiency of hypoxic preconditioning (RF patent no. 2571603).
Our first experiments with the pre-testing intact rats at the PPI model
revealed the oppositely directed cholinergic effects on the HBH efficiency,
separated at the border of PPI=36-40% and the α7 nAChRs participation in both
of them [32,71]. The mechanisms of this phenomenon are unknown. We hope to
clarify this problem somewhat in the neurochemical studies of synaptic pool in
the intact rats pre-tested with PPI.
ACKNOWLEDGEMENT
We are grateful to the direction of Institute of General Pathology and
Pathophysiology that supported and funded our research. And we would like to
thank the team of the Proof-Reading-Service.com and personally Louise Bourdon
for editing and proofreading the English of our manuscript.
RUNNING
HEAD
The hypoxic preconditioning eliminates the innate differences in
resistance to hypoxia and the same preconditioning effect is achieved by
different neuronal pathways.
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