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NEUROPHARMACOLOGY
Department of Biochemistry, Universidad Central del Caribe, Bayamon, Puerto Rico (P.A.F., D.P., V.A.E.); and Mental Retardation Research Center, University of California-Los Angeles, Los Angeles, California (J.d.V.)
Received December 18, 2002; accepted March 11, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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-erythroidine, showing mediation of
neuroprotection by 
42 neuronal nicotinic receptors (nAChRs).
Because nicotine activates 42 and other nAChR subtypes, whereas
10 nM MLA inhibits the 7 subtype, we propose the involvement of a
neuronal circuitry-dependent mechanism for nicotinic neuroprotection. The
effect of nicotine downstream from the receptors was investigated using
inhibitors of cell signaling. The results suggest that the effect of nicotine
is mediated by tyrosine receptor kinases, 1,2-phosphatidylinositol-3 kinase,
and the mitogen-activated extracellular signal-regulated kinases. Although
nicotine neuroprotection is Ca2+-dependent, neither
L-type Ca2+ channels nor calmodulin-dependent protein
kinase is involved in the effect of nicotine. In summary, these results
suggest that in acute slices nicotinic protection is initiated either by
direct activation of 42 or indirectly by inhibition of 7
followed by signal transduction involving tyrosine kinases,
phospholipid-dependent kinases, and mitogen-activated kinases.
; Small et al.,
1997; Wang et al.,
1999; Ferchmin et al.,
2000). As a model of excitotoxic damage, this preparation has the
advantages of an in vitro preparation with most of the circuitry of the
original hippocampus intact as shown by its capability to express complex
functions such as long-term potentiation. In this work, the degree of recovery
from the early electrophysiological damage caused by
N-methyl-D-aspartate (NMDA) is used as a measure of
neuroprotection. The use of PSs to assess the degree of damage has the
advantage that the size of the PS is directly proportional to the number of
functionally active pyramidal neurons
(Andersen et al., 1971). This
acute preparation is well suited to study the early functional neuronal damage
before the onset of cell death. Many neuroprotective drugs and treatments were
evaluated with acute hippocampal slices. Although nicotine and other nAChR
agonists were shown to be neuroprotective in a variety of experimental
systems, they were never studied in acute slices. Nicotine was found to be
neuroprotective in neuronal cultures against glutamate, NMDA, and some of its
analogs (Akaike et al., 1994;
Marin et al., 1994). Nicotinic
neuroprotective activity was reported to be dependent on active 7
nAChRs (Shimohama et al.,
1998) and Ca2+
(Dajas-Bailador et al., 2000;
Kihara et al., 2001). There
are indications that the 42 nAChRs also participate in
neuroprotection (Kihara et al.,
1998). When coapplied with NMDA, nicotine is neuroprotective
without decreasing the NMDA-mediated [Ca2+]i
rise (Minana et al., 1998;
Dajas-Bailador et al., 2000;
Kihara et al., 2001). This
paradox is generated because depending on the pathway of
Ca2+ entry, different downstream effectors are activated
(Bading et al., 1993;
Ghosh and Greenberg, 1995).
Ca2+ is one of the main players in the regulation of
excitotoxicity and neuronal survival. There are several routes of
Ca2+ entry into neurons, of which the NMDA-receptor,
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor, and the
VGCC cannot be ignored, but most relevant for our purpose here are the
neuronal nAChRs 7 and 42. Nicotine-induced
[Ca2+]i increase mediated by 42
or perhaps other heteromeric nAChRs is inhibited by tetrodotoxin, but the
[Ca2+]i increase mediated by 7 is not.
The latter is inhibited by 7 antagonists showing that this receptor
contributes directly to Ca2+ entry, whereas
42 contributes mainly indirectly through VGCC
(Mulle et al., 1992;
Tsuneki et al., 2000).
Ca2+ is a second messenger that regulates many
processes in the brain. Among others, Ca2+ influx
modulates cell signaling by activation of mitogen-activated protein kinases,
leading to adaptive changes that include activation of transcription factors
(Dolmetsch et al., 2001). One
of the branches of mitogen-activated protein kinases, the Raf-MEK-ERK cascade
is usually involved in neuroprotection. Neuronal survival is also promoted, in
a Ca2+-dependent manner, by phosphatidylinositol
3-kinase (PI 3-kinase) (Kihara et al.,
2001; Perkinton et al.,
2002).
This is the first study showing that neuronal function is protected against early electrophysiological NMDA-induced excitotoxic damage by nicotinic effectors in acute hippocampal slices. The pharmacology of the nicotinic neuroprotection is partially elucidated as well as the cell signaling processes downstream from the receptor.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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-bungarotoxin (Btx) were from Calbiochem (La Jolla, CA).
KN-62 was from BIOMOL Research Laboratories (Plymouth Meeting, PA).
(-)-Nicotine di-d-tartrate (nicotine), dihydro--erythroidine
(DHE), and methyllycaconitine (MLA) were from Sigma/RBI (Natick, MA).
NMDA, choline, and genistein were from Sigma-Aldrich.
Slice Preparation and Electrophysiological Recordings. Hippocampal
slices from female Sprague-Dawley rats (120–200 g) from our colony were
prepared and maintained using standard methods. All procedures have been
reviewed and approved by the Institutional Animal Care and Use Committee. For
dissection and incubation, a standard artificial cerebrospinal fluid (ACSF)
was used: 125 mM NaCl, 3.3 mM KCl, 1.25 mM NaH2PO4, 2 mM
MgSO4,2mM CaCl2, 25 mM NaHCO3, and 10 mM
glucose. Dissections were done at ice temperature; transverse slices were cut
400 µm in thickness with a manual slicer and transferred to a chamber. The
lower part of the chamber was filled with H2O kept at 37.4 ±
1°C and continuously bubbled with 95% O2, 5% CO2.
The slices were kept at the gas-liquid interface at 34 ± 1°C on an
acrylic plate covered with a nylon mesh (Hanes) above the H2O.
Before entering the chamber the ACSF was continuously bubbled with 95%
O2, 5% CO2. The exterior of the chamber was kept at 30
± 1°C. Strict control of the temperatures at the three levels
(outside, nylon mesh, and water bath) was indispensable to avoid variability
of results because the toxicity of NMDA is temperature-dependent
(Ferchmin et al., 2000). A
concentric bipolar electrode placed in stratum radiatum was used to stimulate
the slices with a constant current for 0.2 ms. The PSs were recorded in
stratum pyramidale with a glass micropipette filled with 2 M NaCl and
impedance ranging from 1 to 5 M
. The testing of slices started 1 h
after dissection. Each slice was stimulated with a stimulus strength twice
that required to elicit a threshold PS. This initial response was recorded and
compared with the response elicited by the same stimulus and recorded from the
same position 1 h after the corresponding experimental treatment. The
percentage of the initial response remaining at the end of the experiment was
used as a measure of recovery. The incubation chamber contained three lanes
with independent perfusion lines exposed to the same gaseous phase.
Immediately after dissection, 10 to 30 slices were distributed among the three
lanes; when slices from more than one animal were used, they were equally
distributed among the lanes.
Solutions. Dimethyl sulfoxide (DMSO) was routinely used to dissolve hydrophobic inhibitors; therefore, DMSO was added in the same final concentration to the ACSF for all experimental groups in a given experiment. At the concentrations used [<0.1% (v/v)], DMSO had no effect on the recovery of PSs.
Procedure for Testing Neurotoxicity. The procedure was based on
Schurr et al. (1995) as
modified by us (Ferchmin et al.,
2000). Unless otherwise stated, the excitotoxic stimulus used was
the application of 0.5 mM NMDA for 10 min in the presence of 95%
O2, 5% CO2 and 10 mM glucose. Application of 0.5 mM NMDA
for 3 min is known to cause widespread delayed death in neuronal cultures
(Hartley and Choi, 1989). The
relationship between NMDA concentration and loss of PS was standardized to
recover an average of 20% of the PS area
(Ferchmin et al., 2000). The
general experimental design was as follows: 1 h after slice preparation, the
initial PS was recorded. After that, the slices were superfused for 15 min
with a putative inhibitor of nicotine action, followed by nicotine in the
presence of the inhibitor for 1 h, immediately after with 0.5 mM NMDA for 10
min, and then for 1 h with ACSF. Then the final PS was determined. Controls
without inhibitor or without nicotine were perfused with ACSF for the same
amount of time. Variations from this general protocol are indicated under
Results.
Data Analysis. The areas of the PS (millivolts per millisecond) were acquired and analyzed with the Labman program (gift from Dr. T. J. Teyler WWAMI Medical Education Program, University of Idaho, Moscow, ID). The data were statistically analyzed using SigmaStat version 2.03 (SPSS Science, Chicago, IL). Analysis of variance was used whenever the data were distributed normally; otherwise, Kruskal-Wallis one-way analysis of variance on ranks was used followed in each case by the appropriate post hoc test. When two groups were compared, the t test was used.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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E were also without
effect. Btx was tested in experiments of different design. Slices were
stimulated every minute and recording of PSs was done continuously. The first
hour, the slices were kept in normal ACSF, followed by 1 h in 10 nM
Btx, and the last hour in 1 µM Btx. The results of five
independent experiments were averaged. Average areas of the PS after ACSF, 10
nM and 1 µM Btx are, respectively, 10.4 ± 1.1, 9.8 ±
0.7, and 9.6 ± 0.8 mV · ms (mean ± S.E.M.). Incubation of
slices in Ca2+-free ACSF with or without nicotine did
not alter size of the PSs (Fig.
1B).
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To estimate a possible enhancement of NMDA toxicity by the inhibitors of
regulatory kinases and by DHE, they were tested in the presence of 0.2
mM NMDA, a submaximal concentration of NMDA
(Fig. 2). No inhibitor
exacerbated the toxicity of NMDA. On the contrary PD98059 caused a small but
significant neuroprotection (Fig.
2B), whereas Raf-1 inhibitor I showed a trend in the same
direction (Fig. 2E; p
< 0.056).
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The shape of representative population responses is shown
(Fig. 3). Neither NMDA nor
nicotine application produced conspicuous changes in the shapes of the
population responses. The only consistent change was a decreased area of the
PSs in slices exposed to NMDA. The area of the PS is proportional to the
number of pyramidal neurons producing axon potentials
(Andersen et al., 1971). Slices
incubated in ACSF without further treatment conserved most of the area of the
PS at the end of the experiment. After application of NMDA, approximately 20%
of the PS was recovered. However, when 1 µM nicotine was applied for 1 h
before NMDA, the recovery was statistically indistinguishable from
ACSF-incubated slices (Figs. 3A
and 4A).
Ca2+ is one of the main factors involved in neuronal
nicotinic signaling and in excitotoxicity. Therefore, it was of interest to
describe its effect. As expected, NMDA was mostly ineffective when applied in
Ca2+-free ACSF (Fig.
4B). Nicotine applied immediately after NMDA treatment was as
effective as nicotine before NMDA (Fig.
4C). The protective effect of nicotine was partially dependent on
the presence of Ca2+ in the solution
(Fig. 4D).
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The dose dependence of nicotine neuroprotection showed the optimal
concentration near micromolar. Nicotine was neuroprotective from 0.25 to 1
µM, and there was no increase in the neuroprotection from 1 to 10 µM
(Fig. 5). The neuroprotective
effect of nicotine was inhibited by coincubation with 1 µM DHE before
NMDA application (Fig. 6A).
DHE per se did not alter the toxicity of NMDA (Figs.
2C and
6B). Because DHE
inhibited the effect of nicotine, we concluded that the 42
heteromeric subtype is involved.
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Most studies in neuronal cultures have shown that nicotinic neuroprotection
is mediated by the 7 subtype of nAChRs. 7 antagonists were used
to test whether inhibition of 7 receptors affected nicotine
neuroprotection. Btx (1 µM) applied for 1 h did not inhibit the
neuroprotective effect of 1 µM nicotine
(Fig. 7A). In addition, this
toxin had a modest neuroprotective effect in the absence of nicotine. Choline,
a low-affinity 7 agonist, was significantly neuroprotective
(Fig. 7B). Although the
neuroprotection by choline seems to be smaller than that of nicotine, the
difference between the slices pretreated with nicotine and choline was not
significant. DHE only partially decreased the protection exerted by
choline (Fig. 7C).
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To further pursue the role of the 7 receptor, MLA, a specific
7 antagonist was tested. MLA was neuroprotective at 10 nM and 1 µM
when preapplied for 1 h before NMDA (Fig.
8B). The magnitude of neuroprotection exerted by MLA was similar
to that of nicotine (Fig. 8A).
When MLA was coapplied with nicotine, it did not block the neuroprotective
effect of nicotine (Fig. 8C).
As in the case of nicotine, the neuroprotection by MLA was inhibited by 1
µM DHE (Fig. 8D).
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The finding that the neuroprotective effect of nicotine was decreased after
exposure to Ca2+-free ACSF
(Fig. 4D) and effective after
NMDA application (Fig. 4C)
suggested that it triggers a neuroprotective cell-signaling program and that
nicotine does not directly block the NMDA receptor or its effect. To briefly
evaluate the pharmacology of the cell signaling steps involved, inhibitors of
protein kinases were used to inhibit nicotine neuroprotection. The inhibitors
were used at a concentration near 10-fold the IC50 of the intended
target where they are in general regarded as reasonably specific.
Figure 9 shows the effect of
seven inhibitors of cell signaling. Preincubation with 10 or 100 nM K252a, a
nonselective Trk inhibitor (Howe et al.,
2002; Roux et al.,
2002), for 1 h, significantly reduced nicotine-mediated
neuroprotection (Fig. 9, A and
B). The broad-range inhibitor of tyrosine protein kinase,
genistein at 50 µM, also inhibited the neuroportection of nicotine
(Fig. 9C). SU6656 (3 µM), a
Src inhibitor (Blake et al.,
2000), did not affect the neuroprotection by nicotine, suggesting
that Ras phosphorylation by Src is not involved
(Fig. 9D). LY294002 (10 µM)
and 10 nM wortmannin, inhibitors of PI3-kinase that mediates Akt/PKB
activation, robustly inhibited the effect of nicotine
(Fig. 9E). The effective
inhibition of nicotinic neuroprotection by Raf-1 kinase inhibitor I
(Lackey et al., 2000)
(Fig. 9F) and PD98059
(Hetman et al., 1999)
(Fig. 9G) indicate the
involvement of the Raf-MEK-ERK cascade. On the other hand, nifedipine (10
µM), a blocker of L-type VGCC, and the inhibitor of CaM kinase KN-62 (9
µM) (Tokumitsu et al.,
1990) did not decrease the effect of nicotine
(Fig. 10).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Wang et al.,
1999). The comparison of the early effect of experimental ischemia
on the electric activity in acute slices with delayed neuronal death in
cultured slices was consistent with the concept that both represent the same
event in a different time scale (Small et
al., 1997).
Nicotine applied before or after NMDA protected the PSs against NMDA
(Fig. 4, A and D). The effect
of nicotine was tested from 0.1 to 10 µM
(Fig. 5). This range is similar
to the nicotine concentration, from 1 to 100 µM, found to be
neuroprotective in studies with neuronal cultures
(Akaike et al., 1994;
Marin et al., 1994; Kihara et
al., 1998,
2001;
Dajas-Bailador et al., 2000).
Minana et al. (1998) showed
neuroprotection by 10 nM nicotine against glutamate and 10 µM against NMDA.
In our experiments, both the toxic effect of NMDA and the neuroprotective
effect of nicotine were at least in part Ca2+-dependent
(Fig. 4, B and D). The
excitotoxic effect of NMDA and the neuroprotective effect of nicotine that
persisted in Ca2+-free ACSF were probably sustained by
Ca2+ lingering in the slice. It takes about 1 h to reach
equilibrium between the concentration of Ca2+ in the
ACSF and the inside of the slice
(Dingledine and Somjen, 1981).
However, Ca2+-independent effects cannot be discarded at
this time.
The neuroprotective effect of nicotine was not observed in the presence of
1 µM DHE (Fig. 6A).
The Ki of DHE for 42 was estimated to
be from 0.014 to 1.9 µM, for 7 from 25 to 58 µM, and for
34 near 220 µM (Sharples
and Wonnacott, 2001). This demonstrates that active
42 nAChRs are involved.
Unexpectedly, 1 µM Btx applied during 1 h not only did not
inhibit the neuroprotective effect of nicotine but also was neuroprotective
per se (Fig. 7A). To further
study the role of 7 receptors choline was tested. Choline at 10 mM is
an 7 agonist with a possible physiological role
(Alkondon et al., 1999).
Choline applied before NMDA provided neuroprotection comparable with nicotine
(Fig. 7B). In the presence of 1
µM DHE, the neuroprotection exerted by choline significantly
decreased (p < 0.02) but was still significant (p <
0.001) (Fig. 7C). Besides
acting as an agonist, choline also causes desensitization of 7 nAChRs
(Alkondon et al., 1999).
Therefore, choline and Btx could have a similar final effect on the
function of 7 receptors by desensitization and inhibition,
respectively. Because choline is a low-affinity 7 ligand, it is used at
10 mM. However, at this concentration it is likely to have effects unrelated
to nAChRs. Choline blocks the pore of the NMDA receptor
(Villarroel et al., 1995) and
has muscarinic neuroprotective activity
(Minana et al., 1996).
Therefore, choline is not specific enough for mechanistic studies.
MLA is an 7 nicotinic antagonist that diffuses more easily than
Btx because of its smaller molecular weight. MLA from 10 nM to 1 µM
was also neuroprotective per se. This result was reproduced in five
independent experiments with 21 slices per condition in each
(Fig. 8, A–D). The
neuroprotective effect of MLA was inhibited by 1 µM DHE, showing that
MLA neuroprotection requires 42 activity
(Fig. 8D). The
Ki of MLA for the 7 receptor is in the nanomolar
range, whereas the Ki values for 42 and
32 are in the micromolar range
(Sharples and Wonnacott,
2001). Therefore, MLA neuroprotection is mediated by inhibition of
7 nAChRs. This contradicts the work with neuronal cultures
(Minana et al., 1998;
Shimohama et al., 1998;
Dajas-Bailador et al., 2000;
Kihara et al., 2001) where
nicotinic neuroprotection is mediated by 7 activation. There are
several reasons that could account for the difference. The hippocampal slice
has a nearly intact functional neuronal circuitry that is absent in
dissociated neuronal cultures. It is possible that the specific neuronal
circuitry and distribution of nAChRs in the CA1 area are responsible for the
interaction between 7 and 42 nAChRs. However, Prendergast
et al. (2001) reported
inhibition of nicotine-mediated neuroprotection by MLA in organotypic
hippocampal slices. Although, organotypic slices conserve the basic neuronal
circuits, they might have suffered changes in receptor distribution during
maturation in vitro. In addition, the difference between our findings could be
attributed to the variables measured (propidium iodide uptake versus
electrophysiological activity) and the time at which the effect of NMDA is
measured. In acute slices, neuroprotection of the electrophysiological
activity is measured within 2 h after NMDA application, whereas in culture it
is determined 24 h later. Both systems are probably measuring different stages
of the same process.
In conclusion, for this part of the work, the results indicate that
activation of 42 is neuroprotective regardless of the state of
7 activation, whereas the inhibition of 7 is neuroprotective
provided that 42 is not inhibited.
We propose a model that explains these findings (Fig. 11 and legend). This model invokes a highly localized action of nAChRs, thus explaining why a major effect of nicotinic agents alone on the PS area was not seen (Fig. 1). The proposed model might be restricted to electrophysiological parameters of neuroprotection in the area CA1 of acute slices within a limited time window. It remains to be determined whether it will be applicable to delayed neuronal death.
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The fact that the neuroprotective effect of nicotine is
Ca2+-dependent and effective after NMDA application
suggests that nicotine triggers a neuroprotective program involving
neurotrophins and protein kinases. Ca2+ entry increases
the phosphorylation of transcription factors followed by neurotrophin
synthesis (Shieh and Ghosh,
1999). There is evidence that neuroprotection mediated by nAChRs
involves neurotrophins (Belluardo et al.,
2000). The involvement of protein tyrosine kinases in nicotinic
neuroprotection was supported by the inhibitory effect of 50 µM genistein
on the neuroprotection (Fig.
9C). To test for the participation of neurotrophin receptors,
K252a was used. K252a is best known as a Trk inhibitor; however, it also
inhibits other protein kinases. K252a inhibits CaM kinase with an
IC50 value of 1.8 nM (Howe et
al., 2002), mixed lineage kinases with IC50 values of
approximately 5 nM (Roux et al.,
2002), cyclic nucleotide-dependent kinases and protein kinase C
with Ki values ranging from 18 to 25 nM
(Kase et al., 1987), and Trk
kinases with IC50 values of 3 nM
(Tapley et al., 1992). The
inhibition of mixed lineage kinases and CaM kinase is not relevant here. Mixed
lineage kinases are not neuroprotective
(Roux et al., 2002), and CaM
kinase did not mediate nicotinic neuroprotection in our system because KN-62
did not decrease the effect of nicotine
(Fig. 10). A careful analysis
of the inhibition of Trk and kinases of IC50 17 nM or higher
reveals that 10 nM K252a inhibits 77% of the activity of Trk but only 37% of
the other relevant kinases known to be inhibited by K252a. At 100 nM, K252a
inhibits 97% of Trk but also inhibits 86% of protein kinase C and cyclic
nucleotide-dependent kinases. Figure 9, A
and B, shows that decreasing the concentration of K252a from 100
to 10 nM did not decrease the inhibition of the protective effect of nicotine,
suggesting that K252a was inhibiting nicotinic neuroprotection by binding with
high affinity to a relevant kinase likely to be Trk.
Fyn, a subtype of Src, was reported to be involved in nicotinic
neuroprotection in cultured neurons mediated by 7 nAChRs
(Kihara et al., 2001). The
involvement of Src kinase in our system was discarded because SU6656, a
selective inhibitor of the Src family
(Blake et al., 2000), did not
block the effect of nicotine at a concentration 10 times the IC50
value for most Src kinases (Fig.
9D).
The survival-promoting activity of the Trk neurotrophin receptors involves,
among others, the docking of adapter proteins that activate Ras. Ras activates
the PI-3 kinase and the Raf-1, MEK, ERK kinase cascade
(Patapoutian and Reichardt,
2001). Indeed, both cell signaling pathways were involved here.
LY294002 and wortmannin inhibited the effect of nicotine, implicating PI
3-kinase in neuroprotection (Fig.
9E). The effectiveness of Raf-1 kinase inhibitor I
(Fig. 9F) and PD98059
(Fig. 9G) to block the
neuroprotection indicated that the ERK cascade was involved. The simultaneous
involvement of PI-3 kinase and ERK cascades in neuroprotection has been
observed previously (Hetman et al.,
1999). Calcium signaling mediated by L-type channels and CAM
kinase was reported to lead to survival in cultured neurons
(Dolmetsch et al., 2001).
However, neither nifedipine nor the CAM kinase inhibitor KN-62 blocked the
effect of nicotine in our preparation
(Fig. 10).
In conclusion, we propose a neuroprotective cell signaling pathway
triggered by the activation of nAChRs. Ca2+ entry,
mediated directly or indirectly by 42 nAChRs, enhances the
signaling through Trk receptors, leading to Ras activation. Ras leads to
activation of PI 3-kinase and the Raf-1-MEK-ERK cascade known to promote
neuroprotection.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: PS, population spike; NMDA,
N-methyl-D-aspartate; nAChR, nicotinic acetylcholine
receptor; [Ca2+]i, intracellular calcium
concentration; VGCC, voltage-gated Ca2+ channel; MEK,
mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated
kinase; PI 3-kinase, phosphatidylinositol 3-kinase; Btx,
-bungarotoxin; DHE; dihydro--erythroidine; MLA,
methyllycaconitine; ACSF, artificial cerebrospinal fluid; DMSO, dimethyl
sulfoxide; CaM kinase, calmodulin-dependent protein kinase; SU6656,
2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylene)-2,3-dihydro-1H-indole-5-sulfonic
acid dimethylamide; LY 294002,
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; PD98059,
2'-amino-3'-methoxyflavonone, KN-62,
1-[N,O-bis(5-isoquinolinsulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine;
K252a,
(8R,9S,11S)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,910-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclo-octa(cde)trinden-1-one.
Address correspondence to: P. A. Ferchmin, Department of Biochemistry, Universidad Central Del Caribe, P.O. Box 60-327, Bayamon, Puerto Rico 00960-6032. E-mail: ferchmin{at}coqui.net or ferchmin{at}uccaribe.edu
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, p < 0.05. The number of slices per experimental group
was n = 14 (A), n = 21 (B), n = 14 (C), and
n = 28 (D).
