CNS Drug Reviews

Vol. 12, No. 1, pp. 1–8

© 2006 The Authors
Journal compilation © 2006 Blackwell Publishing Inc.

Bryostatin-1: Pharmacology and

Therapeutic Potential as a CNS Drug

Miao-Kun Sun and Daniel L. Alkon

Blanchette Rockefeller Neurosciences Institute, Rockville, MD, USA

Keywords: Alzheimer’s disease — Antidepressants — Bryostatin-1 — Cognition activation —

Depression — Learning and memory — Mood — Protein kinase C.

ABSTRACT
Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at
nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been fo-
cused on its action in preventing tumor growth. Emerging evidence suggests, however,
that bryostatin-1 exhibits additional important pharmacological activities. In preclinical
studies bryostatin-1 has been shown at appropriate doses to have cognitive restorative and
antidepressant effects. The underlying pharmacological mechanisms may involve an acti-
vation of PKC isozymes, induction of synthesis of proteins required for long-term
memory, restoration of stress-evoked inhibition of PKC activity, and reduction of neuro-
toxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic po-
tential of bryostatin-1 as a CNS drug should be further explored.

INTRODUCTION
The bryostatins, a family of at least 20 marine natural products with a chemical
structure of macrocyclic polyketides, were first isolated from the bryozoan Bugula neriti-
na by Pettit et al. in 1968 and characterized chemically in 1982 (33). Their main pharma-
cological mechanism of action is modulation of protein kinase C (PKC) activity. The pro-
totypic member, bryostatin-1 (Fig. 1) possesses a unique pharmacological profile as a
cancer chemotherapeutic. It is currently in phases I and II trials against a variety of
cancers (8,13,19,27) and produces behavioral and cognitive effects when appropriate drug
levels are achieved in the brain (14,39). It inhibits tumor invasion, tumor growth in vitro
and in vivo, and angiogenesis. It also synergizes with other anticancer agents (2), reverses
multidrug resistance (3,37), stimulates the immune system (11), enhances cognition, and
has antidepressant effects.
The focus of this short review is on pharmacology of bryostatin-1 and evaluation of its
therapeutic potential in the treatment of dementia and depression.
Address correspondence and reprint requests to: Miao-Kun Sun, Ph.D., Blanchette Rockefeller Neurosciences
Institute, 9601 Medical Center Drive, Academic and Research Bldg., Room 319, Rockville, MD 20850, USA.
Phone: +1 (301) 294-7181, Fax: +1 (301) 294-7007, E-mail: mksun@brni-jhu.org

1
2 M-K. SUN AND D. L. ALKON

OH
O 11 OAc

B A
O O O

3 1 O

OH H
OH
O O
19
C 26
O OH

O
O

O
FIG. 1. Chemical structure of bryostatin-1.

PHARMACODYNAMICS

Bryostatin-1 is a partial agonist of several members of the PKC family (see below). Its
pharmacological effects appear to depend on its action on the PKC isozymes. Bryostatin-1
binds PKC isozymes with IC50 subnanomolar concentrations and a dissociation half-time
of several hours [12]. The binding of bryostatin-1 to PKC results in PKC activation, auto-
phosphorylation, and translocation to the cell membrane. Bryostatin-1-bound PKC is then
downregulated by ubiquitination and degradation in proteasomes. Downregulation is most
significant when the PKC isozymes are exposed to high and/or prolonged high concentra-
tions of bryostatin-1. It should be, however, mentioned here that modulation of PKC ac-
tivity may not be the only biological action of bryostatins (25). For example, in B16/F10
melanoma cells (26) epi-bryostatin-1, a bryostatin-1 stereoisomer, with much lower af-
finity for PKC, exhibits the same potency in inhibiting cell growth as bryostatin-1 (41),
suggesting the involvement of aPKC activity-independent action. Nevertheless, modu-
lation of PKC activity is the only well established biological mechanism by which bryo-
statin-1 produces a variety of biological effects.
Bryostatin-1 can modulate the activity of two of the three subgroups of PKC isozymes.
PKC activity, with the active site of isozymes usually located at the C-terminus, is in-
volved in the phosphorylation of serine and threonine residues. PKC isozymes are divided
into three subgroups, which differ in their molecular structures and co-factor require-
ments: classical PKC (cPKC; á, âI, âII, and ã isoforms), novel PKC (nPKC; ä, å, å¢, ç, è,
and ì isoforms), and atypical PKC (aPKC; æ and ë/i). The cPKC and nPKC contain regu-
latory C1 domains (C1A and C1B) and are activated by diacylglycerol, phorbol esters, and
bryostatins. The difference between cPKC and nPKC is that cPKC has a C2 region corre-
sponding to the Ca2+ binding site and requires Ca2+ as a co-factor for activation, whereas
the nPKC does not contain the C2 region and, therefore, does not require Ca2+ as a co-
factor for activation. The third group, aPKC, does not bind phorbol esters or bryostatins

CNS Drug Reviews, Vol. 12, No. 1, 2006

 BRYOSTATIN-1 3

and contains no C2 region and one of the repeated cysteine-rich zinc finger binding motifs
within the C1 domain. Bryostatin-1 is, therefore, expected to modulate nPKC activity, in-
dependent of a Ca2+ signal. It activates cPKC only when associated with Ca2+ signaling.
aPKC activity is not sensitive to bryostatin-1 administration. Interestingly, Ca2+ signals
play an important role in synaptic transmission and information processing. Bryostatin-1
thus possesses a unique action profile: it will not affect cPKC activity in neurons that are
not functioning as an active part of the signaling processing circuit with significant Ca2+
influx and intracellular Ca2+ release.
Studies of structure-activity relations of bryostatin-1 (Fig. 1) for PKC isoforms (44–46)
indicate that the intact 20-membered macrolactone ring is needed for good PKC binding
activity while the A-ring and the B-ring exocyclic olefin can be deleted from the 20-mem-
bered structure without inducing much change in PKC-binding affinity. The C[26] free
hydroxyl is essential for a good interaction with the PKC isozymes, while the C[1] car-
bonyl group is also important for a high affinity (44). The C[19] hydroxyl group may be
involved in the interaction with the lipid bilayer during binding, while the C[3] hydroxyl
group plays an important role in the conformation of the molecule. The A-ring region can
be extensively modified without affecting binding affinity. Thus the C[9] region could be
modified as needed to tune ADME (absorption, distribution, metabolism, and excretion)
and pharmacokinetic characteristics (46). The C[20] region is a non-pharmacophoric site
and can also be modified to tune analogs for function and physical properties without sig-
nificantly affecting their binding affinity for the PKC isozymes (44). These positions can
thus be used to change for improvement of physical properties and selectivity, and for in-
corporation of additional functionality, such as a fluorophore.
Bryostatin-1 can mimic certain effects of phorbol esters in some biological systems.
However, several other properties of bryostatin-1 are distinct from those of the phorbol
esters (22). Of critical importance and unlike the phorbol esters, this compound lacks tu-
mor-promoting capabilities and actually counteracts tumor promotion induced by phorbol
esters (17), an important pharmacological property when clinical potential is considered.

Role in Alzheimer’s Disease

Numerous reports (10,16,24) imply a critical role of deficient functions of PKC iso-
zymes in the pathogenesis of Alzheimer’s disease (AD). Intensive efforts have, therefore,
been focused on the development of bryostatin-1 and its analogs to treat dementia of the
Alzheimer’s type.
AD, a devastating and progressive decline of memory and other cognitive functions
(e.g., a reduced ability to learn, loss of memory, decreased attention, judgment, and deci-
sion-making), robs the affected individuals of quality of life. The main histopathological
hallmarks of AD brain are extracellular senile plaques and intracellular neurofibrillary
tangles at late stages of the disorder, particularly in the hippocampus and related neural
structures that play an essential role in memory formation. Three pharmacological profiles
favor potential use of bryostatin-1 and its analogs to restore cognitive dysfunction espe-
cially that associated with AD.
1) PKC isozymes are activated by synaptic inputs and intracellular signals that are in-
volved in information processing and play an important role in various types of learning
and memory (4,6). Reduced PKC activity is associated with AD (10,16), at least partially
due to a direct inhibition of PKC activity by neurotoxic Aâ (24). Activation of PKC with
bryostatin-1 induces the de novo synthesis of proteins necessary and sufficient for subse-

CNS Drug Reviews, Vol. 12, No. 1, 2006

4 M-K. SUN AND D. L. ALKON

quent long-term memory consolidation in Hermissenda (5). PKC inhibition, on the other
hand, impairs learning and memory. Mice deficient in PKCb have been found to show
normal brain anatomy and normal hippocampal synaptic transmission, paired facilitation,
and long-term potentiation of the glutamatergic synaptic responses but a loss of learning
in both cued and contextual fear conditioning (42). Bryostatin-1 selectively activates
cPKC isozymes in those neurons that are active, as part of the information processing net-
work with Ca2+ signaling. Activation of PKC with bryostatin-1 promotes stabilization of
growth-associated protein 43 (GAP-43) mRNA, resulting in an increased GAP-43 protein
level in human neuroblastoma cells (34). In addition, evidence has been provided that
bryostatin-1, at appropriate doses (bilateral intracerebroventricular 0.64 or 2 pmoles/site),
directly enhances learning and memory in Wistar rats (39).
2) Activation of certain PKC isozymes has therapeutic values in reducing the for-
mation of extracellular senile plaques, one of the AD’s main histopathological hallmarks.
Bryostatin-1 activates á-secretase, probably through PKC á, ä, or å (14,21,47,50). At sub-
nanomolar concentrations, it enhances the secretion of á-secretase product soluble amylo-
id precursor protein (sAPP)á in fibroblasts from AD patients and reduces brain Aâ40 and
Aâ42 accumulation in AD double-transgenic mice (14). In APP[V7171] transgenic mice,
PKC activation has also been found to reduce Aâ40 accumulation in the brain (14).
3) PKC activation inhibits glycogen synthase 3 kinase (15,23) and thereby reduces ô
protein hyperphosphorylation (7) and intracellular neurofibrillary tangles, another main
histopathological hallmark of AD.
The combination of memory-enhancing action and reduction in brain amyloid burden
and ô protein hyperphosphorylation may represent a promising multi-target strategy with
one agent and an effective therapeutic approach against AD.

Role in Depression
Mood disorders are among the most prevalent forms of mental illness. They are re-
current, life threatening (due to the risk of suicide), and a major cause of morbidity
worldwide. Several forms of depression affect 2–5% of the U.S. population, and up to
20% of this population suffers from milder forms of the illness. Efforts to enhance mono-
amine activity in the brain pharmacologically have led to the development of several clini-
cally effective antidepressants. Unfortunately, progress in the development of new and im-
proved antidepressants has been limited. The new drugs developed so far have essentially
the same mechanism of action as the older ones and, as a result, the efficacy of the newer
agents and the ranges of depressed patients they treat are no better than those of the older
drugs. Today’s treatment thus remains suboptimal, with only ~50% of all patients demon-
strating complete remission, although many more (up to 80%) show partial response. In
addition, the current pharmacological treatments, including the use of the second gener-
ation of antidepressants, selective serotonin reuptake inhibitors, are associated in some
cases with a disturbing “impulsive” tendency for suicide. The adverse effects as well as
limited antidepressant efficacy of the available drugs call for new antidepressants.
It is of interest that dementia and depression appear to share common structural and
signal pathway injuries (38). An involvement of PKC activity in depression and its treat-
ment has been implicated in several studies. PKC may be involved in 5-hydroxytrypt-
amine (5-HT2A) receptor desensitization (35). Activation of the hypothalamic-pituitary-
adrenal axis causes downregulation of PKC isozymes in rat brain (30). Reduced PKC ac-
tivity occurs in the prefrontal cortex and the hippocampus in suicide victims (28,31,32)

CNS Drug Reviews, Vol. 12, No. 1, 2006

 BRYOSTATIN-1 5

and in fibroblasts cultured from skin biopsies from patients with melancholic depression
(1). The human plasma membrane serotonin transporter is a substrate for PKC. PKC acti-
vation or phosphatase inhibition downregulate uptake of 5-HT. This effect is probably me-
diated by reduction of the expression of 5-HT transporter (36). Imipramine, a tricyclic
antidepressant, but not citalopram, has been shown to increase PKC levels in primary rat
neuronal cultures (29). Along this line of an important role of PKC activity in mood regu-
lation is the observation that bryostatin-1, at appropriate doses, has antidepressant activity
in rats (39). In an open space swim model of induced depressive behavior, bryostatin-1, at
100 nmoles/kg i.v., significantly reduced non-searching immobility in rats. This antide-
pressant effect of bryostatin-1 is largely abolished by co-administration of 1-(5-isoquino-
linesulfonyl)-2-methylpiperazine (H-7), a PKC inhibitor, suggesting the involvement of
PKC activation in its antidepressant action. It is, therefore, likely that bryostatin-1 and/or
its analogs could be developed as new antidepressants.

PHARMACOKINETICS

In clinical trials as an antitumor agent, bryostatin-1 is given either as a bolus intra-

venous injection or a continuous infusion. It is difficult to perform pharmacokinetic
analysis of bryostatin-1 in humans as its in vivo blood levels are not easily detectable by
mass spectrometry or high-performance liquid chromatography. Trial design has been
hampered by lack of human pharmacokinetic data. Efforts have been made to develop
more specific and sensitive methods for detection of bryostatin-1 in human plasma (49).
These efforts may lead to an improvement in the design of future trials.
Pharmacokinetics of bryostatin-1 has been, however, studied in animals. In mice,
studies with [C26-3H]bryostatin-1, i.v. or i.p. reveal a wide distribution of the drug with
high levels in lungs, liver, gastrointestinal tract, and fat (48), whereas its oral bioavailabil-
ity, to our knowledge, has not been clearly established. Bryostatin-1 is relatively stable to
metabolic breakdown in vivo. High-performance liquid chromatography analysis indicates
that radioactivity is mainly associated with the intact molecule, suggesting that the com-
pound remained largely intact. Following intravenous administration to mice, the plasma
disappearance curve of bryostatin-1 fits a two compartment model, with half-lives of 1.05
and 22.97 h, respectively. In contrast, the plasma disappearance curve for bryostatin-1 ad-
ministered i.p. is better described by a first order absorption one-compartment model, with
an absorption half-life of 0.81 h and an elimination half-life of 28.76 h, respectively. The
majority of radioactivity in plasma was associated with the intact drug for up to 24 h after
dosing. During the first 12 h after i.v. administration of bryostatin-1, urinary excretion rep-
resented the major pathway of drug elimination, with 23.0 ± 1.9% (mean ± S.D.) of the
administered dose excreted. Within 72 h after i.v. administration, approximately equal
amounts of radioactivity (40%) were excreted in feces and in urine.
After i.v. administration of bryostatin-1 to mice, a brief increase in its brain levels was
observed, reaching several nanomoles after an i.v. dose of 40 mg/kg (48). These brain
levels were sufficient to activate PKC isozymes that were sensitive to bryostatin-1, but the
brain levels rapidly declined after administration of the drug. After i.p. injection of the
same dose to mice, on the other hand, the peak brain levels were much lower, but the in-
creases were longer-lasting than those observed after an i.v. dose. These data indicate that
bryostatin-1 can pass through the blood-brain barrier, although the brain levels of the drug
were much lower than its plasma levels (48).

CNS Drug Reviews, Vol. 12, No. 1, 2006

6 M-K. SUN AND D. L. ALKON

ADVERSE EFFECTS AND HUMAN TOXICITY

The maximum tolerated dose of bryostatin-1 in humans has been found to be about
25 ìg/m2/week, given intravenously over up to 8 weeks (9,20,26). Toxic and adverse re-
actions are rare and generally mild. Myalgia is the dose-limiting toxicity in humans.
Myalgia occurs at one to two days after infusion and tends to get worse with repeated ad-
ministration. The symptoms are eased by exercise but return on resting. The calves, thighs
and extraocular muscles are affected first but myalgia becomes more generalized as
therapy continues. Myalgia affecting the muscles of hypopharynx may result in frontal
headache and odynophasia. Lasting impairment of oxidative metabolism in muscle mito-
chondria may be responsible for myalgia (18). Other reported adverse reactions in humans
include fatigue and lethargy; they are common but generally mild. Less common adverse
effects include low-grade pyrexia, nausea and anorexia. In a toxicological study in rats, le-
thargy, unsteadiness, and hematuria have also been observed following bryostatin-1 treat-
ment. Adverse hematological toxicities in humans are not common, although thrombocy-
topenia and leucopenia have been reported. Mild abnormalities of liver function have also
been reported. Bryostatin-1 toxicity appears to be age-dependent. Children can tolerate
higher doses of the drug. The maximal tolerated dose of bryotaxin-1 in children has been
reported to be 44 ìg/m2 (43). Myalgia and photophobia are the dose limiting toxic effects
of bryostatin-1 in children. It remains to be determined whether the age-dependent toxicity
of bryostatin-1 would limit its utility in aged AD patients.

CONCLUSIONS
Several studies have suggested that at appropriate doses bryostatin-1 can produce bene-
ficial effects on cognition and mood, through modulation of PKC activity. Activation of
PKC isozymes represents a potential therapeutic strategy in improving memory and mood,
although we do not know precisely which PKC isozyme(s) may mediate the observed ef-
fects. PKC isozymes are involved in a variety of vital functions and neurological disorders
so that a long-term PKC activation may cause wide and severe reactions. For instance, all
forms of PKC isozymes are sensitive to oxidative stress. It remains to be studied whether a
sustained increase in the plasma levels of bryostatin-1 would further sensitize PKC isozy-
mes to oxidants. However, intermittent PKC activation with lower doses over an extended
period may avoid such reactions. Multiple but intermittent doses of bryostatin-1 or its ana-
logs, administered chronically, are expected to result in brief but multiple “peaks” of PKC
activation with smaller doses, maximizing effects of PKC cascade activation but mini-
mizing potential “tolerance” or PKC downregulation that is associated with the exposure
to high and/or long-lasting high concentrations of bryostatin-1. Based on the data avail-
able in clinical trials, bryostatin-1 is well tolerated as an antitumor agent. This means that
its adverse side effects are rare, generally mild, and reversible. It possesses several phar-
macological actions, including functional restoration of a reduced PKC signal cascade that
occurs in dementia and depression, a reduction in the accumulation of neurotoxic amyloid,
and an inhibition of tau protein hyperphosphorylation. Structural modifications of bryosta-
tin-1 may lead to compounds that possess bryostatin-1 activity but can pass through the
blood-brain barrier much easier, so that they may achieve the desired brain effects at
smaller doses. Bryostatin-1 and its analogs (44,46) may be developed as therapeutic drugs
for the treatment of dementia, depression, and/or disorders such as attention-deficit/hyper-

CNS Drug Reviews, Vol. 12, No. 1, 2006

 BRYOSTATIN-1 7

activity disorder in which cognitive enhancement is desirable and co-morbid depression is

prominent.

REFERENCES
1. Akin D, Hal Manier D, Sanders-Bush E, Shelton RC. Signal transduction abnormalities in melancholic de-
pression. Int J Neuropsychopharmacol 2005;8:5–16.
2. Ali S, Aranha O, Li YW, Pettit GR, Sarkar FH, Philip PA. Sensitization of human breast cancer cells to
gemcitabine by the protein kinase C modulator bryostatin-1. Cancer Chemother Pharm 2003;52:235–246.
3. Al-Katib AM, Smith MR, Kamanda WS, et al. Bryostatin-1 down-regulates mdr1 and potentiates vincristine
cytotoxicity in diffuse large cell lymphoma xenografts. Clin Cancer Res 1998;4:1305–1314.
4. Alkon DL, Nelson TJ, Zhao WQ, Cavallaro S. Time domains of neuronal Ca2+ signaling and associative
memory: Steps through a calexcitin, ryanodine receptor, K+ channel cascade. Trends Neurosci 1998;21:
529–537.
5. Alkon DL, Epstein H, Kuzirian A, Bennett M. C, Nelson TJ. Protein synthesis required for long-term
memory is induced by PKC activation on days before associative learning. Proc Natl Acad Sci USA 2005;
102:16432–16437.
6. Bank B, DeWeer A, Kuzirian AM, Rasmussen H, Alkon DL. Classical conditioning induces long-term
translocation of protein kinase C in rabbit hippocampal CA1 cells. Proc Natl Acad Sci USA 1988;85:
1988–1992.
7. Cho JH, Johnson GV. Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ.
J Biol Chem 2004;279:54716–54723.
8. Clamp A, Jayson GC. The clinical development of the bryostatins. Anti-Cancer Drugs 2002;13:673–683.
9. Clamp AR, Blackhall FH, Vasey P, et al. A phase II trial of bryostatin-1 administered by weekly 24-hour in-
fusion in recurrent epithelial ovarian carcinoma. Br J Cancer 2003;89:1152–1154.
10. Cole G, Dobkins KR, Hansen LA, Terry RD, Saitoh T. Decreased levels of protein kinase C in Alzheimer
brain. Brain Res 1988;452:165–174.
11. Curiel RE, Garcia CS, Farooq L, Aguero MF, Espinoza-Dagado I. Bryostatin-1 and IL-2 synergize to induce
IFN-gamma expression in human peripheral blood T cells: Implications for cancer immunotherapy. J Immu-
nol 2001;167:4828–4837.
12. de Vries D, Herald CL, Pettit HG, Blumberg PM. Demonstration of sub-nanomolar affinity of bryostatin-1
for the phorbol ester receptor in rat brain. Biochem Pharmacol 1988;37:4069–4073.
13. Dowlati A, Lazarus HM, Hartman P, et al. Phase I and correlative study of combination bryostatin-1 and vin-
cristine in relapsed B-cell malignancies. Clin Cancer Res 2003;9:5929–5935.
14. Etcheberrigaray R, Tan M, Dewachter I, et al. Therapeutic effects of PKC activators in Alzheimer’s disease
transgenic mice. Proc Natl Acad Sci USA 2004;101:11141–11146.
15. Fang X, Yu S, Tanyi JL, Lu Y, Woodgett JR, Mills GB. Convergence of multiple signaling cascades at gly-
cogen synthase kinase 3: Edg receptor-mediated phsophorylation and inactivation by lysophosphatidic acid
through a protein kinase C-dependent intracellular pathway. Mol Cell Biol 2002;22:2099–2110.
16. Favit A, Grimaldi M, Nelson TJ, Alkon DL. Alzheimer’s-specific effects of soluble â-amyloid on protein
kinase C-á and -ã degradation in human fibroblasts. Proc Natl Acad Sci USA 1998;10:5562–5567.
17. Hennings H, Blumberg PM, Pettit GR, Herald CL, Shores R, Yuspa SH. Bryostatin-1, an activator of protein
kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 1987;8:
1343–1346.
18.18. Hickman PF, Kemp GJ, Thompson CH, et al. Bryostatin-1, a novel antineoplastic agent and protein kinase
C activator, induces human myalgia and muscle metabolic defects: A 31P magnetic resonance spectroscopic
study. Br J Cancer 1995;72:998–1003.
19. Hofmann J Protein kinase C isozymes as potential targets for anticancer therapy. Curr Cancer Drug Targets
2004;4:125–146.
20. Jayson GC, Crowther D, Prendiville J, et al. A phase I trial of bryostatin-1 in patients with advanced malig-
nancy using a 24 hour intravenous infusion. Br J Cancer 1995;72:461–468.
21. Kinouchi T, Sorimachi H, Maruyama K, et al. Conventional protein kinase C (PKC)-alpha and novel PKC
epsilon, but not –delta, increase the secretion of an N-terminal fragment of Alzheimer’s disease amyloid pre-
cursor protein from PKC cDNA transfected 3Y1 fibroblasts. FEBS Lett 1995;364:203–206.
22. Kraft AS, Reeves JA, Ashendel CL. Differing modulation of protein kinase C by bryostatin-1 and phorbol
esters in JB6 mouse epidermal cells. J Biol Chem 1988;263:8437.
23. Lavoie L, Band CJ, Kong M, Bergeron JJM, Posner BI. Regulation of glycogen synthase in rat hepatocytes.
Evidence for multiple signaling pathway. J Biol Chem 1999;274:28279–28285.

CNS Drug Reviews, Vol. 12, No. 1, 2006

8 M-K. SUN AND D. L. ALKON

24. Lee W, Boo JH, Jung MW, et al. Amyloid beta peptide directly inhibits PKC activation. Mol Cell Neurosci
2004;26:222–231.
25. Matthews SA, Pettit GR, Rozengurt E. Bryostatin-1 induces biphasic activation of protein kinase D in intact
cells. J Biol Chem 1997;272:20245–20250.
26. Mutter R, Wills M. Chemistry and clinical biology of the bryostatins. Bioorg Med Chem 2000;8:1841–1860.
27. Nezhat F, Wadler S, Muggia F, et al. Phase II trial of the combination of bryostatin-1 and cisplatin in
advanced or recurrent carcinoma of the cervix: A New York Gynecologic Oncology Group Study. Gynecol
Oncol 2004;93:144–148.
28. Pacheco MA, Stockmeier C, Meltzer NY, Overholser JC, Dilley GE, Jope RS. Alterations in phosphoinosi-
tide signaling and G-protein levels in depressed suicide brain. Brain Res 1996;723:37–45.
29. Pákáski M, Bjelik A, Hugyecz M, Kása P, Janka Z, Kálmán J. Imipramine and citalopram facilitate amyloid
precursor protein secretion in vitro. Neurochem Intern 2005;47:190–195.
30. Pandey GN, Dwivedi Y. Effects of adrenal glucocorticoid on protein kinase C (PKC) binding sites, PKC ac-
tivity and expression of PKC isozymes in the brain. J Neurochem 2000;74:S21D.
31. Pandey GN, Dwivedi Y, Ren X, et al. Altered expression and phosphorylation of myristoylated alanine-rich
C kinase (MARCKS) in postmortem brain of suicide victims with or without depression. J Psychiatr Res
2003;37:421–432.
32. Pandey GN, Ewivedi Y, Rizavi HS, Ren X, Conley RR. Decreased catalytic activity and expression of
protein kinase C isozymes in teenage suicide victims. Arch Gen Psychiatry 2004;61:685–693.
33. Pettit GR, Herald CL, Doubek DL, Arnold E, Clardy J. Isolation and structures of bryostatin-1. J Am Chem
Soc 1982;104:6846–6848.
34. Pascale A, Amadio M, Scapagnini G, et al. Neuronal ELAV proteins enhances mRNA stability by a PKCá-
dependent pathway. Proc Natl Acad Sci USA 2005;102:12065–12070.
35. Rahimian R, Hrdina PD. Possible role of protein kinase C in regulation of 5-hydroxytryptamine 2A re-
ceptors in rat brain. Can J Physiol Pharmacol 1995;73:1686–1691.
36. Ramamoorthy S, Giovanetti E, Qian Y, Blakely RD. Phosphorylation and regulation of antidepressant-sen-
sitive serotonin transporters. J Biol Chem 1998;273:2458–2466.
37. Spitaler M, Utz I, Hilbe W, Hofmann J, Grunicke HH. PKC-independent modulation of multidrug resistance
in cells with mutant (V185) but not wild-type (G185) P-glycoprotein by bryostatin-1. Biochem Pharm 1998;
56:861–869.
38. Sun M-K, Alkon DL. Depressed or demented: Common CNS drug targets?! Curr Drug Targets. CNS Neurol
Disord 2002;1:573–589.
39. Sun M-K, Alkon DL. Dual effects of bryostatin-1 on spatial memory and depression. Eur J Pharmacol
2005;512:43–51.
40. Sun M-K, Alkon DL. Protein kinase C isozymes: Memory therapeutic potential. Curr Drug Targets. CNS
Neurol Disord 2005;4:541–52.
41. Szallasi Z, Du L, Levine R, et al. The bryostatins inhibit growth of B16/F10 melanoma cells in vitro through
a protein kinase C-independent mechanism: Dissociation of activities using 26-epi-bryostatin-1. Cancer Res
1996;56:2105–2111.
42. Weeber EJ, Atkins CM, Selcher JC, et al. A role for the b isoform of protein kinase C in fear conditioning.
J Neurosci 2000;20:5906–5914.
43. Weitman S, Langevin AM, Berkow RL, et al. A phase I trial of bryostatin-1 in children with refractory solid
tumors: A pediatric oncology group study. Clin Cancer Res 1999;5:2344–2348.
44. Wender PA, Baryza JL, Bennett CE, et al. The practical synthesis of a novel and highly potent analogue of
bryostatin. J Am Chem Soc 2002;124:13648–13649.
45. Wender PA, Baryza JL. Identification of a tunable site in bryostatin analogs: C20 bryologs through late stage
diversification. Org Lett 2005;7:1177–1180.
46. Wender PA, Clarke MO, Horan JC. Role of the A-ring of bryostatin analogues in PKC binding: Synthesis
and initial biological evaluation of new A-ring-modified bryologs. Org Lett 2005;7:1995–1998.
47. Yeon SW, Jung MW, Ha MJ, et al. Blockade of PKC epsilon activation attenuates phorbol ester-induced
increase of alpha-secretase-derived secreted form of amyloid precursor protein. Biochem Biophys Res
Commun 2001;280:782–787.
48. Zhang X, Zhang R, Zhao H, et al. Preclinical pharmacology of the natural product anticancer agent bryo-
statin-1, an activator of protein kinase C. Cancer Res 56:802–808,1996.
49. Zhao M, Rudek MA, He P, Smith, BD, Baker S.D.. Validation and implementation of a method for determi-
nation of bryostatin-1 in human plasma by using liquid chromatography/tandem mass spectrometry. Ann
Biochem 337:143–148,2005.
50. Zhu G, Wang D, Lin YH, McMahon T, Koo EH, Messing RO. Protein kinase C epsilon suppresses Abeta
production and promotes activation of á-secretase. Biochem Biophys Res Commun 2001;285:997–1006.

CNS Drug Reviews, Vol. 12, No. 1, 2006