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Protein Kinase C Activators as Synaptogenic and Memory Therapeutics.

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Arch. Pharm. Chem. Life Sci. 2009, 342, 689 – 698
M.-K. Sun and D. L. Alkon
Protein Kinase C Activators as Synaptogenic and Memory
Miao-Kun Sun and Daniel L. Alkon
Blanchette Rockefeller Neurosciences Institute, Rockville, MD, USA
The last decade has witnessed a rapid progress in understanding of the molecular cascades that
may underlie memory and memory disorders. Among the critical players, activity of protein kinase C (PKC) isoforms is essential for many types of learning and memory and their dysfunction,
and is critical in memory disorders. PKC inhibition and functional deficits lead to an impairment of various types of learning and memory, consistent with the observations that neurotoxic
amyloid inhibits PKC activity and that transgenic animal models with PKCb deficit exhibit
impaired capacity in cognition. In addition, PKC isozymes play a regulatory role in amyloid production and accumulation. Restoration of the impaired PKC signal pathway pharmacologically
results in an enhanced memory capacity and synaptic remodeling / repair and synaptogenesis,
and, therefore, represents a potentially important strategy for the treatment of memory disorders, including Alzheimer’s dementia. The PKC activators, especially those that are isozyme-specific, are a new class of drug candidates that may be developed as future memory therapeutics.
Keywords: Isoforms / Memory disorders / PKC activators / Protein kinase C / Signaling /
Received: March 10, 2009; Accepted: July 16, 2009
DOI 10.1002/ardp.200900050
Protein kinase C (PKC) isoforms are important signaling
molecules, mediating various extracellular signals into
the cell and triggering intracellular signaling events [1].
They are ubiquitously expressed in the central nervous
system and are activated by either Ca2+, phospholipids
and diacylglycerol, phorbol-esters, or other agents [2].
The PKC signaling pathway plays an important and regulatory role in a wide range of vital biological functions
and processes [3–5], such as proliferation, altered gene
expression, synaptic plasticity, neuronal injury, synaptic
remodeling/repairing and synaptogenesis, differentiation, cell growth and apoptosis, and oncogenesis.
With respect to memory and memory disorders, it is
well established that PKC isoforms play an important
Correspondence: Miao-Kun Sun, Blanchette Rockefeller Neurosciences
Institute, Rockville, MD 20850, USA.
Fax: +1 301 294-7007
Abbreviations: Alzheimer's disease (AD); long-term depression (LTD);
protein kinase C (PKC); classical/novel/atypical protein kinase C (c/n/
(DCP-LA); receptors for activated C-kinase (RACKs)
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
functional role in controlling memory-relevant signaling
process. The brain, especially in the vital neural structures that are involved in cognition and mood regulation, contains the highest concentration of PKC in the
body [6]. Accumulating evidence points to an important
role of various isoforms of PKC in the formation of memory traces and of their functional insufficiency in pathogenesis of memory disorders. Restoration of PKC activity
and signaling cascades pharmacologically thus represents a potentially important opportunity in the development of novel cognitive therapeutic agents. In this short
review article, we intend to briefly summarize the roles
of PKC isoforms in learning and memory and neural
injury, and to indicate the potential of developing memory therapeutic candidates that act on the PKC signaling
Protein kinase C isoforms and signaling
PKC activity, with the active site located near the C-terminus to phosphorylate serine and threonine residues of
target proteins, is mediated by a family of at least twelve
PKC isoforms [7–9] (Fig. 1), each of which is encoded by a
M.-K. Sun and D. L. Alkon
Arch. Pharm. Chem. Life Sci. 2009, 342, 689 – 698
Figure 1. PKC isozyme family.
separate gene, with the exception of the bI and bII isoforms as splice variants. The twelve PKC isoforms are further divided into three subgroups, classical PKCs (cPKCs),
novel PKCs (nPKCs), and atypical PKCs (aPKCs), based on
their molecular structures and, thus, co-factor requirements for activation. Structurally, PKCs all contain two
catalytic domains that functions as a serine / threonine
kinase (the ATP-binding site-containing C3, and the substrate-binding site-containing C4 domains), interspaced
by the isozyme-unique (variable or V) regions, and a pseudosubstrate sequence adjacent to the C1 domain (Fig. 1).
The N-terminal pseudosubstrate motif binds to the catalytic domain in the inactive state, functioning as an autoinhibitory domain of PKCs. The difference between the
PKC isoforms is mainly the regulatory domain. The cPKCs
contain two main regulatory domains, the activatorbinding C1 domain and the C2 region corresponding to
the Ca2+ binding site [10], and requires Ca2+ as a co-factor
for activation, and consists of a, bI, bII, and c isoforms.
The C1 domains represent zinc-finger structures that
bind diacylglycerol and other non-Ca2+ PKC activators
and are also able to bind alcohols and anesthetics [11].
The nPKCs, including d, e, e9, g, h, and l isoforms, on the
other hand, do not have the Ca2+-binding C2 region [11–
13], and thus are Ca2+-independent for activation. The
nPKCs contain a C2-like structure, which may be involved
in interaction with proteins and phospholipids. The
cPKCs and nPKCs contain both C1A and C1B subdomains
and can all be activated by diacylglycerol, phorbol esters,
and bryostatins. Each of the C1 subdomains interacts
with sn-1,2-diacylglycerol and phorbol esters [14–16],
often with different affinities depending on the isozymes. The C1A domain of PKCd, for example, has high
affinity for diacylglycerol and is critical for the diacylglycerol-induced membrane binding and PKCd activation,
while the C1B domain exhibits high affinity for phorbol
esters [17]. These differences indicate potential for developing isozyme-selective PKC activators. The third group,
aPKCs, includes f and k/i isoforms, containing a PB1
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
domain involved in protein-protein interaction and a single C1 domain that does not bind diacylglycerol, phorbol
esters, or bryostatins. aPKCs do not contain the Ca2+-binding C2 region and one of the repeated cysteine-rich zincfinger binding motifs within the C1 domain [18, 19] and
appear to have higher structural restriction for activators
than the other subgroups. Evidence has been provided
that atypical PKCf, whose expression levels are correlated
with nucleotide excision repair activity and protein levels, probably regulates the expression of nucleotide
repair proteins [20].
Many of the PKC isoforms are co-expressed in the same
cells. Largely due to a lack of water-soluble, PKC isoformspecific inhibitors, we do not know in many cases which
particular PKC isozyme(s) mediates the observed effects.
It is known, however, that PKCs are activated by synaptic
inputs and intracellular signals involved in information
processing in cognition, including glutamatergic inputs
[21], cholinergic inputs [22], serotonergic inputs [23, 24],
dopaminergic inputs [25], intracellular calcium and diacylglycerol elevations, and hormones [26]. PKCs control
membrane electrical properties [27, 28] and modulate
neurotransmitter receptor function [29–31]. Activation
of PKCs leads to changes in such vital responses as
enhancing calcium action potentials, increasing neurotransmitter release [32–34], and decreasing voltage-gated
Na+ currents [22–24] and voltage-dependent K+ currents
[35–40] as well as calcium-activated potassium current in
the hippocampus, all relevant to information processing
in cognition. Phorbol esters, for instance, have been
shown to increase the size of the readily releasable transmitter pool and the rate at which the pool refills at glutamatergic hippocampal synapses [32]. PKC modulates the
glutamatergic, GABAergic, and cholinergic systems. PKC
activation with 12-O-tetradecanoylphorbol has been
shown to modify both a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate receptor (AMPAR) and N-methyl-Daspartate receptors (NMDAR) mobility and to increase
their extrasynaptic and synaptic diffusion /
Arch. Pharm. Chem. Life Sci. 2009, 342, 689 – 698
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
localized to the membranes of axonal processes, and is
not found in membranes of dendritic processes ([64–66],
except in the olfactory system [67]). Transgenic mice overexpressing GAP-43 have been found to exhibit an
enhanced memory in a spatial maze task [62], while heterozygous GAP-43 knockout mice exhibit impaired hippocampus-dependent memory [68]. The separate localization of PKCs and their membrane-associated substrates,
such as GAP-43, in the neurons requires an essential step
in the PKC activation, i. e., translocation. PKC activation
in associative learning [35] is indeed associated with a
characterized PKC translocation from cytosol to membrane component [69, 70]. The PKC translocation from
the cytoplasm to the membrane component of the neurons is associated with phosphorylation of GAP-43 on its
Ser-41 in rats, mice, and humans and Ser-42 in chicks and
with the induction of long-term potentiation (LTP) [71].
The phenomenon of PKC translocation occurs presynaptically, as in the case of phosphorylation of GAP-43 [56]
and LTP [72], as well as postsynaptically, as in the case of
associative learning [69].
In learning and memory, it is generally believed that
the frequency and intensity of calcium spikes / waves represent important signals of the experienced events. PKCs
can detect’ the calcium-spike frequency and intensity,
thus the pattern and frequency of synaptic inputs, in a
unique pattern and cycle of calcium-induced translocation and diacylglycerol-mediated kinase activation
[73, 74]. cPKC is not activated when calcium spikes are
absent whereas other calcium-independent PKC isoforms
respond to signal events without associated calcium
tion [41, 42]. Metabotropic GluR (mGluR)6-containing
kainate receptors are probably the trigger for PKC-mediated inhibition of slow after-hyperpolarization in the
hippocampal CA1 pyramidal neurons [43]. Glutamate
also desensitizes mGluR5a and mGluR5b, through PKCmediated phosphorylation of mGluR5 at multiple sites
[44]. PKC activity plays an important regulatory role in
GABAergic synaptic transmission [45] and also appears to
mediate brain-derived neurotrophic factor (BDNF)induced modulation of GABAA receptor phosphorylation
and activity [46]. Choline acetyltransferase, which synthesizes acetylcholine in the cholinergic neurons, is differentially phosphorylated by PKC isoforms on four serines
(Ser-440, -346, -347, -476) and one threonine (Thr-255),
regulating its catalytic activity [47].
These functional changes are likely associated with
morphological changes, including synaptic remodeling
and synaptogenesis, which are also induced by PKC activation. Neurotrophic activity and other stimuli cause a
transient increase in levels of cellular diacylglycerol,
which activates PKC as well as produces some other PKCindependent effects [48]. Activation of PKCa, for instance,
promotes protein synthesis and spine formation through
Hu proteins (mRNA-stabilizing proteins ELAV [49, 50]).
Local astrocytic contact of hippocampal neurons activates PKC through arachidonic acid cascade in neurons,
triggering excitatory synaptogenesis [51, 52]. The cascade
represents an underlying mechanism for global neuronal maturation following local astrocyte adhesion, probably including neurogenesis in adults such that matured
hippocampal astrocytes regulate neurogenesis by
instructing stem cells to adopt a neuronal fate [53, 54]. In
the cultured hippocampal neurons, for example, activation of PKC induces rapid morphological plasticity in
dendrites and spines [55]. The same type of responses has
also been observed in vivo [56, 57]. Interestingly, not only
does synaptic facilitation and synaptogenesis involve
PKC activation, synaptic activity-induced synapse elimination may also involve PKC. One possibility is that different isoforms may be involved. PKCh in both presynaptic
and postsynaptic elements has been proposed to play an
important role in activity-dependent synaptic elimination at the neuromuscular synapse [58].
In addition to the elements in transmitter systems, synapses and receptor / channels, PKCs can also regulate synaptogenesis and interact with a large diverse family of
PKC-interacting proteins [4, 59–63], such as the growthassociated protein, GAP-43, and the receptors for activated C-kinase (RACKs), including the myristoylated alanine-rich C kinase substrate (MARCKS). GAP-43, whose
expression is up-regulated during spatial learning and
memory [49], is found exclusively in the brain [61], is
Protein Kinase C Activators
Protein kinase C and memory / memory
PKC activity is involved in synaptic plasticity including
LTP [75–78] and long-term depression (LTD) [79, 80]. However, the PKC effects on LTP of the glutamatergic synapses
may not necessarily mean corresponding effects on cognition. Dissociation of memory performance from LTP
has been observed and reported frequently. For instance,
mice with deficits in PKCb have been found to show normal brain anatomy and normal hippocampal synaptic
transmission, normal paired facilitation, and normal LTP
of the glutamatergic synaptic responses, but a loss of
learning and memory in both cued and contextual fear
conditioning [81].
PKC activity plays an important role in learning and
memory, and in memory disorders. PKC activity is
involved in many types of cognitive tasks, including
M.-K. Sun and D. L. Alkon
Arch. Pharm. Chem. Life Sci. 2009, 342, 689 – 698
Table 1. Evidence involving PKC isozymes in memory and memory disorders.
Major findings
Brain expression
The highest levels exist in the hippocampus and related brain structures
that are involved in learning and memory.
Associative learning induces translocation of PKC from the cytosolic to
membrane compartments in the hippocampal CA1.
PKC activation enhances spatial learning and memory, synaptic remodeling /
repairing, synaptogenesis, and protein synthesis. Enhanced PKC activity also
reduces amyloid formation and tau hyperphosphorylation, and increases
amyloid degradation.
PKC inhibitors impair learning and memory, including passive avoidance
and spatial learning and memory.
PKC isozymes are functionally vulnerable to neurotoxic amyloid, including
amyloid oligomers.
Transgenic mice with PKCb deficits exhibit a loss of learning in cued and
contextual fear conditioning. Reduced PKC activity also occurs in patients
with AD.
Activation in learning
PKC activators
PKC inhibition
PKC vulnerability
PKC deficits
learning and memory of eye-blink conditioning [82–86],
spatial learning and memory [69, 87–92], olfactory-discrimination learning [93], conditioned-taste aversion
[94], contextual-fear memory [95, 96], cues-provoked
cocaine memory performance [97], and conditioned
avoidance [98]. A persistent phosphorylation by PKMf, an
autonomously active PKC isoform, has been reported critical for aversive long-term memories, such as place avoidance in the hippocampus [99] and conditioned-taste aversion in the neocortex [100].
The involvement of PKC activity in memory and memory disorders is implicated by several factors (Table 1).
First, the brain, especially the hippocampus and related
structures that play critical roles in cognition, expresses
the highest levels of PKC in the body. Second, neural
events and activated inputs that occur in learning and
memory activate PKC. Associative learning produces
translocation of PKC activity from the cytosolic to the
membrane compartment of the CA1 region of the hippocampus [69]. Third, PKC activation with bryostatin-1 has
been found to enhance synaptogenesis, presynaptic
ultrastructural specialization, and protein synthesis that
are involved in spatial maze learning and memory
[56, 101]. Fourth, activation of PKC improves spatial
learning and memory. Bryostatin-1, a PKC activator,
enhances spatial memory in rats [102]. Fifth, PKC inhibition and functional deficits impair cognition. Reduced
PKC activity is associated with Alzheimer's disease (AD)
[103, 104], suggesting an involvement in cognition.
PKCb, for instance, has been found to predominantly
express in the neocortex, in area CA1 of the hippocampus, and in the basolateral nucleus of the amygdala in
mice [81]. Mice with deficits in PKCb have been found to
exhibit a loss of learning in both cued and contextual
fear conditioning [81]. Furthermore, age-related spatial
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
[56, 101, 102, 124–
128, 130–132, 147]
[102, 113]
[104, 119, 120, 121,
[81, 103, 104, 108,
memory impairment is associated with altered subcellular concentrations of PKCc and may be indicative of deficient signal transduction and neuronal plasticity in the
hippocampal formation. The connection between PKC
and memory and dementia is illustrated by decreased
PKCb and e levels and activities in the temporal cortex
[105, 106] without changes in PKCb mRNA [107] and in
crude extracts from the hippocampus, temporal and
frontal cortex [108]. Hippocampal membranes of AD
brains have been reported to show a reduced membrane
fluidity in the hydrocarbon core region [109], a changed
membrane environment that may affect PKC activation.
It has been shown that activity of PKC enzyme extract
purified from endogenous modulators is not modified in
all brain areas of AD patients [110], suggesting either
changed isoform degradation or increased endogenous
inhibitors of PKC activity in the AD brain. Another important change in AD brains is RACKs, the substrate for activated PKCs. RACKs are important regulators of PKC function [111]. Deficit in RACK1 levels has been reported in
both soluble and particulate fractions from AD brain
frontal cortex [112].
There are numerous reports that dysfunction of PKC is
associated with the development of AD and other neurodegenerative disorders, raising the hypothesis that PKCsignaling deficits and impaired synaptic remodeling /
synaptogenesis may underlie AD pathogenesis. PKC
inhibition and functional impairment have been consistently found to significantly impair performance of cognitive tasks. Intracerebroventricular injection of PKC
inhibitors, for example, causes marked memory impairment in passive avoidance task and water maze task
[113]. The hippocampus in mammals is involved in many
types of cognitive performance as well as mood regulation [114–117] and plays a critical role in episodic,
Arch. Pharm. Chem. Life Sci. 2009, 342, 689 – 698
Protein Kinase C Activators
tion of the PKC cascades lead to an improved information
processing and synaptic remodeling as those are involved
as necessary in learning and memory. A second therapeutic action involves a restoration of PKC activity. The interaction between PKC and Ab suggests that restoration of
the inhibited PKC activity may have direct therapeutic
effects on cognition. A third potentially important action
of PKC in antidementia is its role in regulation and modulation of amyloid production. Activation of PKCa and e is
known to enhance sAPPa production [124, 125] and thus
to reduce Ab formation [126]. Evidence has been provided
that the administration of bryostatin-1, a potent PKC activator, reduces Ab40 in the brains of AD transgenic mice
and both brain Ab40 and Ab42 in AD double-transgenic
mice [127]. The action has an obvious therapeutic value
for bryostatin-1 to be an antidementic agent, as long as
neurotoxic amyloid defines much of the pathogenesis of
AD. In addition, overexpression of PKCe has been found to
increase endothelin converting enzyme activity and to
reduce amyloid plaque pathology in transgenic mice
expressing familial AD-mutant forms of the human APP
[128]. Some of this apparent therapeutic benefit of bryostatin-1 may be produced through its persistent activation
of PKCd in the absence of down-regulation of the isoform
[129]. Furthermore, evidence is available indicating that
PKC activation inhibits glycogen synthase 3 kinase
[130, 131] and, thereby, reduces tau hyperphosphorylation [132]. This last event is considered important for the
production of another pathologic hallmark of AD: neurofibrillary tangles.
Figure 2. PKC activators.
ative, and spatial learning and memory [118]. Expression
of PKC isozymes and their functions, especially those in
the hippocampus and related brain structures, are plastic and vulnerable to various factors, such as stress and
neurotoxic amyloid [119, 120]. Amyloid-b peptide (Ab)
contains a PKC pseudosubstrate domain (Ab 28-30) and
can directly inhibit PKC isozymes, including PKCa and
PKCe [104, 121]. Ab thus directly blocks PKC activation,
induces PKC degradation [104], reduces PKC-mediated
phosphorylation [122, 123], and decreases PKC membrane translocation [120]. Some of the AD neuropathology and functional impairment in cognition may be
mediated by this Ab-induced PKC inhibition.
PKC activators may produce antidementic and memory-facilitating effects through several actions. One
important antidementic action of PKC activation could be
to facilitate PKC translocation that has been observed to
occur in a variety of associative memory tasks [102]. Activa-
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PKC activators
Recent evidence supports the notion that PKC activators
are promising therapeutic candidates that may be developed to drugs for memory and memory disorders. This is
based on the pharmacological profiles of these agents,
including a facilitation of synaptic plasticity, an enhancement of learning and memory, restoration of an
impaired PKC signaling activity, a reduction in neurotoxic amyloid production and accumulation, and an
inhibition of tau hyperphosphorylation.
Diacylglycerol, arachidonic acid, phorbol esters, bryostatins, aplysiatoxins, teleocidins, epigallocatechin gallate, and 8-[2-(2-pentylcyclopropylmethyl)-cyclopropyl]octanoic acid (DCP-LA) are PKC activators (Fig. 2), with differences in isoform-selectivity and binding affinities. The
majority of these activators bind to a hydrophilic cleft in
a largely hydrophobic surface of the C1 domains, resulting in an enhanced hydrophobicity of the surface and
promoting the interaction between the C1 domain and
M.-K. Sun and D. L. Alkon
the phospholipid bilayer of the cell membranes and driving removal of the pseudosubstrate region from the catalytic site of the enzyme. DCP-LA, a linoleic acid derivative,
on the other hand, has been shown to selectively activate
PKCe, possibly through binding to the phosphatidylserine binding site [133].
Recent studies point to reliable memory-facilitating
and antidementic effects of bryostatins. Bryostatin-1
[134, 135], a macrocyclic lactone (Fig. 2) isolated from the
marine Bugula neritina [135], is an antineoplastic agent
that potently activates PKC with a chemical structure
unrelated to phorbol esters. Pharmacologically, bryostatin-1 acts as a partial agonist and can selectively modulate PKC isozymes, including PKCa, PKCd, and PKCe [136–
139], at very low concentrations (at nM or sub-nM concentrations) but prevents tumor cell growth, probably
through a selective down-regulation of PKCa in several
cancer cell lines [140, 141] and prevention of certain
PKCd from undergoing down-regulation [142]. Activation
of PKC with bryostatin-1 enhances learning and memory,
induces protein synthesis and synaptic remodeling / synaptogenesis, activates a-secretase, and, thus, reduces the
production and accumulation of neurotoxic amyloid
[126, 127]. These pharmacological profiles make it an
especially attractive lead for the design of new PKC activators. The binding of bryostatin-1 to sensitive PKC isoforms results in PKC activation, autophosphorylation,
and translocation to the cell membrane. The PKC activation leads to its substrate phosphorylation and a variety
of cellular responses. Bryostatin-1-bound PKC is then
down-regulated by ubiquitination and degradation in
proteasomes. Not surprisingly, short exposures to bryostatin-1 activate PKC, while prolonged exposures are followed by down-regulation of PKC. Down-regulation is
most significant when PKC is exposed to high and/or prolonged high concentrations of bryostatin-1 [136, 137,
143, 144]. Studies of structure-activity relations of bryostatins for PKC isoforms [145, 146] reveal that effective
PKC binding activity requires the intact 20-membered
macrolactone ring, while the A-ring and the B-ring exocyclic olefin can be deleted from the 20-membered structure without inducing much change in PKC-binding
affinity. The C(3)-hydroxyl with (R)-stereochemistry is
important for a high affinity, while the C(26) free
hydroxyl is essential for a good interaction with PKC isozymes. In rats, administration of bryostatin-1 (either i.v.
or i.p.), especially at an intermittent dosing, has been consistently found to enhance spatial learning and memory
[56, 102, 147] and a spatial memory-specific increase in
mushroom spine, effects that are sensitive to PKC inhibition [56]. The anti-apoptic and synaptogenesis-facilitating
action of ryostatin-1 may be valuable for the treatment of
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2009, 342, 689 – 698
memory impairments in cerebral ischemia / stroke [57]
and neurodegenerative disorders, including AD [148].
Diacylglycerol is an endogenous PKC activator, binding to the C1 domain of cPKC and nPKC, with binding
affinity at lM levels (for displacing bound [20-3H]phorbol
12,13-dibutyrate [149]). The hydrocarbon chains of diacylglycerol are to facilitate partitioning into the lipid-rich
membrane environment. Phorbol esters, such as phorbol
12,13-dibutyrate and phorbol 12-myristate 13-acetate
(Fig. 2), also bind to the C1 domain of cPKC and nPKC,
with binding affinities over two orders of magnitude
greater than those of diacylglycerol. The higher potencies of phorbol esters are derived from a conformationally rigid orientation of hydrophilic pharmacophores.
There are reports, however, that some observed effects
that are produced with phorbol esters and viewed as PKCdependent may be mediated by other signaling molecules, such as MUNC13, not by PKC [19, 150].
(–)-Epigallocatechin gallate, the most active polyphenolic constituent of green tea, has been shown to activate
PKC, facilitating a presynaptic glutamate release [151].
Activation of PKC isozymes leads to an enhanced learning and memory in control rodents and decreased memory deficits in those with cognitive impairment. Most of
the PKC activators can penetrate the blood-brain barrier
when administered peripherally, though pharmacokinetic data are rather limited, especially in humans. Animal studies with an i.v. administration of bryostatin-1,
for instance, reveal a brief increase in its brain level, a
two-compartment model of plasma disappearance (with
half-live of 1.05 and 22.97 h), and a wide distribution
(with high levels in lungs, liver, gastrointestinal tract,
and fat [138]). The compound remains largely intact in
the body for up to 24 h, with urinary excretion being the
major pathway of drug elimination. In clinical trials as
an antitumor agent, the maximally tolerated i.v. dose of
bryostatin-1 has been found to be about 25 lg/m2/per
week over up to eight weeks [152]. Toxic and side effects
are rare and generally mild, with myagia being the doselimiting reaction in humans. The main concern related
to the development of bryostatin-1 and its analogues to
therapeutic drugs is that PKC activity is involved in a variety of functions and neurological disorders. It remains to
be demonstrated whether a relatively non-selective activator of this pathway would be clinically useful without
producing serious adverse effects. PKCa, b, e, and f, for
instance, function as suppressors of apoptosis, whereas
PKCd, h are pro-apoptotic in function [153–161]. Furthermore, the PKCd is implicated in heart failure and myocardial hypertrophy. Inhibition of PKCd and activation of
PKCe appear to protect against myocardial ischemia, but
a low level of PKCd activation is essential to maintain
Arch. Pharm. Chem. Life Sci. 2009, 342, 689 – 698
mal cardiomyocyte cytoskeletal integrity [162]. In addition, the C1 domain structures [19] also exist in other
molecules, such as PKD kinases [163], chimaerin Rac
GTPase-activating proteins [164], Ras guanyl nucleotidereleasing protein [165], Ras and Rap1 exchange factors,
MUNC13 scaffolding proteins [149], and diacylglycerol
kinases b and c [176]. Agents acting on the C1 domain
may, therefore, produce effects through PKC-independent pathways. These concerns, including impact on cardiovascular function [167–169], may only be addressed
when more studies are performed to define the PKC isoform involvement in particular actions, and when more
selective PKC isoform activators and inhibitors are developed and tested. DCP-LA, through binding to the phosphatidylserine binding site, may be pharmacologically
beneficial because of its non-C1 domain-binding, isoform-selectivity for PKCe and is worth further investigation.
Concluding remarks
Activation of the PKC isozymes represents an attractive
therapeutic strategy in improving memory. There is no
doubt that PKCs play an important role in learning and
memory and that agents acting on the PKC signal cascade(s) have promising therapeutic values in antidementic therapy. The phorbol esters have been reported to be
potent PKC stimulators. However, their potential as therapeutic drugs is limited by their action as tumor promoters [170]. Unlike the phorbol esters, bryostatin-1 lacks
tumor-promoting capabilities and actually counteracts
tumor promotion induced by phorbol esters [171]. In clinical trials as an antitumor agent, bryostatin-1 is reasonably well tolerated [152]. The pharmacological advantages possessed by bryostatins are exciting. Small and
intermittent doses are needed to produce memoryenhancing and antidementic effects in rodents. However,
their selectivity for PKC isoforms is still rather limited.
With this regards, DCP-LA may have advantage for its isoform-selectivity and binding to a different site. It remains
to be studied whether this higher isoform selectivity
leads to a more desired pharmacological profile. Nevertheless, it has also been shown that PKC activators have
powerful antidementic / memory-enhancing activities in
animal models [102, 172, 173] and that the ligand-binding sites of the PKC isozymes possess some different profiles so that highly potent isozyme-selective PKC activators may be developed in the near future [174–176]. With
a full understanding of the intracellular targets of individual PKC isozymes in different cell types [177], the use
of pharmacological or molecular therapeutic approaches
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Protein Kinase C Activators
based on modulation of PKC activity / cascades might be
justified clinically in the future.
The authors have declared no conflict of interest.
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