Bryostatin-1 attenuates intestinal ischemia/reperfusion-induced intestinal barrier dysfunction, inflammation, and oxidative stress via activation of Nrf2/HO-1 signaling.

Bryostatin-1 (Bryo-1) exerts antioxidative stress effects in multiple diseases, and we confirmed that it improves intestinal barrier dysfunction in experimental colitis. Nevertheless, there are few reports on its action on intestinal ischemia/reperfusion (I/R). In this study, we mainly explored the effect of Bryo-1 on intestinal I/R injury and determined the mechanism. C57BL/6J mice underwent temporary superior mesenteric artery (SMA) obturation to induce I/R, on the contrary, Caco-2 cells suffered to oxygen and glucose deprivation/reperfusion (OGD/R) to establish the in vitro model. RAW264.7 cells were stimulated with LPS to induce macrophage inflammation. The drug gradient experiment was used to demonstrate in vivo and in vitro models. Bryo-1 ameliorated the intestinal I/R-induced injury of multiple organs and epithelial cells. It also alleviated intestinal I/R-induced barrier disruption of intestines according to the histology, intestinal permeability, intestinal bacterial translocation rates, and tight junction protein expression results. Bryo-1 significantly inhibited oxidative stress damages and inflammation, which may contribute to the restoration of intestinal barrier function. Further, Bryo-1 significantly activated Nrf2/HO-1 signaling in vivo. However, the deletion of Nrf2 in Caco-2 and RAW264.7 cells attenuated the protective functions of Bryo-1 and significantly abolished the anti-inflammatory effect of Bryo-1 on LPS-induced macrophage inflammation. Bryo-1 protects intestines against I/R-induced injury. It is associated with intestinal barrier protection, as well as inhibition of inflammation and oxidative stress partly through Nrf2/HO-1 signaling.

Biological evaluation of indolactams for in vitro bryostatin 1-like activity.

Small molecule activators of protein kinase C (PKC) have traditionally been classified as either tumor promoters or suppressors. Although bryostatin 1 has well established anti-cancer activity, most natural products that target the PKC regulator domain exhibit tumor promotion properties. In this study, we examine a focused library of indolactam analogues in cell-based assays to establish the structural features of the scaffold that enhance bryostatin 1-like activity. These systematic biological assessments identified specific indole substitution patterns that impart diminished tumor promotion behavior in vitro for indolactam analogues, while still maintaining nanomolar potency for PKC.

The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has been characterized so far, describing either impaired expression or altered activity of single PKC isozymes (α, ß, ζ and δ). Here, we detailed the distribution and cellular localization of the ε-isozyme of protein kinase C (PKCε) in human postmortem motor cortex specimens and reported a significant decrease in both PKCε mRNA (PRKCE) and protein immunoreactivity in a subset of sporadic ALS patients. We furthermore investigated the steady-state levels of both pan and phosphorylated PKCε in doxycycline-activated NSC-34 cell lines carrying the human wild-type (WT) or mutant G93A SOD1 and the biological long-term effect of its transient agonism by Bryostatin-1. The G93A-SOD1 cells showed a significant reduction of the phosphoPKCε/panPKCε ratio compared to the WT. Moreover, a brief pulse activation of PKCε by Bryostatin-1 produced long-term survival in activated G93A-SOD1 degenerating cells in two different cell death paradigms (serum starvation and chemokines-induced toxicity). Altogether, the data support the implication of PKCε in ALS pathophysiology and suggests its pharmacological modulation as a potential neuroprotective strategy, at least in a subgroup of sporadic ALS patients.

Anti-Alzheimer's Molecules Derived from Marine Life: Understanding Molecular Mechanisms and Therapeutic Potential.

Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most common cause of dementia. It has been confirmed that the pathological processes that intervene in AD development are linked with oxidative damage to neurons, neuroinflammation, tau phosphorylation, amyloid beta (Aß) aggregation, glutamate excitotoxicity, and cholinergic deficit. Still, there is no available therapy that can cure AD. Available therapies only manage some of the AD symptoms at the early stages of AD. Various studies have revealed that bioactive compounds derived from marine organisms and plants can exert neuroprotective activities with fewer adverse events, as compared with synthetic drugs. Furthermore, marine organisms have been identified as a source of novel compounds with therapeutic potential. Thus, there is a growing interest regarding bioactive compounds derived from marine sources that have anti-AD potentials. Various marine drugs including bryostatin-1, homotaurine, anabaseine and its derivative, rifampicins, anhydroexfoliamycin, undecylprodigioisin, gracilins, 13-desmethyl spirolide-C, and dictyostatin displayed excellent bioavailability and efficacy against AD. Most of these marine drugs were found to be well-tolerated in AD patients, along with no significant drug-associated adverse events. In this review, we focus on the drugs derived from marine life that can be useful in AD treatment and also summarize the therapeutic agents that are currently used to treat AD.

Evaluation of Toxic Amyloid 42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator.

Amyloid ß42 (Aß42), a causative agent of Alzheimer's disease (AD), is derived extracellularly from Aß precursor protein (APP) following the latter's cleavage by ß-secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing Aß production. Since Aß42 oligomer formation causes potent neurotoxicity, APP modulation by PKC ligands is a promising strategy for AD treatment. Although bryostatin-1 (bryo-1) is a leading compound for this strategy, its limited natural availability and the difficulty of its total synthesis impedes further research. To address this limitation, Irie and colleagues have developed a new PKC activator with few side effects, 10-Me-Aplog-1, (1), which decreased Aß42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKCε-dependent Aß-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known ß-secretase stabilizer, was reduced by treatment with 1. Notably, 1 prevented the formation of intracellular toxic oligomers. Furthermore, 1 suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that 1 was not neurotoxic toward either cell line, these findings suggest that 1 is a potential drug lead for AD therapy.

Bryostatin-1 ameliorated experimental colitis in Il-10-/- Mice by protecting the intestinal barrier and limiting immune dysfunction.

Bryostatin-1 (Bry-1) has been proven to be effective and safe in clinical trials of a variety of immune-related diseases. However, little is known about its effect on Crohn's disease (CD). We aimed to investigate the impact of Bry-1 on CD-like colitis and determine the mechanism underlying this effect. In the present study, 15-week-old male Il-10-/- mice with spontaneous colitis were divided into positive control and Bry-1-treated (Bry-1, 30 µg/kg every other day, injected intraperitoneally for 4 weeks) groups. Age-matched, male wild-type (WT) mice were used as a negative control. The effects of Bry-1 on colitis, intestinal barrier function and T cell responses as well as the potential regulatory mechanisms were evaluated. We found that the systemic delivery of Bry-1 significantly ameliorated colitis in Il-10-/- mice, as demonstrated by decreases in the disease activity index (DAI), inflammatory score and proinflammatory mediator levels. The protective effects of Bry-1 on CD-like colitis included the maintenance of intestinal barrier integrity and the helper T cell (Th)/regulatory T cell (Treg) balance. These effects of Bry-1 may act in part through nuclear factor erythroid 2-related factor 2 (Nrf2) signalling activation and STAT3/4 signalling inhibition. The protective effect of Bry-1 on CD-like colitis suggests Bry-1 has therapeutic potential in human CD, particularly given the established clinical safety of Bry-1.

Bryostatin-1 inhibits cell proliferation of hepatocarcinoma and induces cell cycle arrest by activation of GSK3ß.

Bryostatin-1, a macrolide lactone derived from marine organism Bugula neritina, has been shown to inhibit carcinogenesis in several prospective clinical trials. In the current study, the therapeutic potential of bryostatin-1 in inhibiting proliferation of hepatocarcinoma was evaluated by in vitro and in vivo studies. The mechanisms of action of bryostatin-1 were predicted by in silico assay and further validated by surface plasmon resonance and western blot assay. Our results show that bryostatin-1 (100, 200 nM) treatment can suppress cell proliferation and induce G1 cell cycle arrest in PLC/PRF/5 and SMCC7721 cell. We also found a significant inhibitory action of bryostatin-1 (100, 200 nM) on CyclinD1 activity in PLC/PRF/5 cells, and bryostatin-1 can promote ubiquitination-dependent protein degradation of CyclinD1 in PLC/PRF/5 cells. Western blot results confirmed that the active form phospho-GSK3ß Tyr216 expression was increased significantly after bryostatin-1 treatment. Activation of GSK3ß might be responsible for bryostatin-1 induced cyclinD1 degradation and cell cycle arrest. Taken together, bryostatin-1 may inhibit HCC cells proliferation by promoting cyclinD1 proteolysis and inducing cell cycle arrest.

Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents.

Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub-nanomolar concentrations (0.03-0.3 nM), bryostatin-1 and its synthetic analog, picolog (0.1-10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation. Bryostatin-1 treatment stabilized human skin equivalents (HSEs), a bioengineered combination of primary human skin cells (keratinocytes and dermal fibroblasts) on an extracellular matrix composed of mainly collagen. Fibroblasts activated by bryostatin-1 protected the structural integrity of HSEs. Bryostatin-1 and picolog prolonged activation of Erk in fibroblasts to promote cell survival. Chronic stress promotes the progression of apoptosis. Dermal fibroblasts constitutively express all components of Fas associated apoptosis, including caspase-8, an initiator enzyme of apoptosis. Prolong bryostatin-1 treatment reduced apoptosis by decreasing caspase-8 and protected dermal fibroblasts. Our data suggest that bryostatin-1 and picolog could be useful in anti-aging skincare, and could have applications in tissue engineering and regenerative medicine.

Protein kinase C activator bryostatin-1 modulates proteasome function.

Proteasome activity in ubiquitin-proteasome pathway plays a pivotal role in degradation and clearance of aggregated, oxidized, damaged, and misfolded unwanted proteins to control protein homeostasis or proteostasis. Proteasome activity decreases with cellular senescence, aging, and age-related diseases. Therefore, enhancement of impaired proteasome function by molecular biological and/or pharmacological intervention is an active area of research. Bryostatin-1, a naturally occurring macrocyclic lactone, activates PKC isozymes (specifically, -α and -ϵ) at sub-nanomolar concentrations, but downregulates at higher concentrations. Here, we present bryostatin-1 increased chymotrypsin-like proteasome activity of 20S assembly at sub-nanomolar to nanomolar concentrations (0.3-30 nM). However, proteasome activity decreased at a micromolar concentration of bryostatin-1 (AG08044 cultured skin: P < 0.005; differentiated SH-SY5Y cells: P < 0.02). Modulation of proteasome function by bryostatin-1 was studied in six dermal fibroblast primary cell lines developed both from freshly taken biopsies from healthy donors (n = 2) and obtained from well-characterized cell repositories (n = 4; without any diseases). Bryostatin-1 enhanced proteasome activity in cultured skin fibroblasts obtained from banked and freshly isolated skin fibroblasts from skin biopsies at the sub-nanomolar concentration (P < 0.015). Modulation of proteasome function by bryostatin-1 was confirmed in neuron-like differentiated SH-SY5Y cells. Direct additions of bryostatin-1 into cell lysates prepared from neuron-like differentiated SH-SY5Y, Jurkat cells, and cultured skin fibroblasts were unable to increase proteasome activity indicating that bryostatin-1 can only modulate proteasome activity when added to live cell culture systems. Standard PKC inhibitors blocked bryostatin-1 induced proteasome activity modulation suggesting that enhancement of proteasome activity was mediated by PKC modulation.

Methods behind oncolytic virus-based DC vaccines in cancer: Toward a multiphase combined treatment strategy for Glioblastoma (GBM) patients.

Glioblastoma (GBM) remains an orphan cancer disease with poor outcome. Novel treatment strategies are needed. Immunotherapy has several modes of action. The addition of active specific immunotherapy with dendritic cell vaccines resulted in improved overall survival of patients. Integration of DC vaccination within the first-line combined treatment became a challenge, and immunogenic cell death immunotherapy during chemotherapy was introduced. We used a retrospective analysis using real world data to evaluate the complex combined treatment, which included individualized multimodal immunotherapy during and after standard of care, and which required adaptations during treatment, and found a further improvement of overall survival. We also discuss the use of real world data as evidence. Novel strategies to move the field of individualized multimodal immunotherapy forward for GBM patients are reviewed.

Adoptive immunotherapy with cells from tumor-draining lymph nodes activated and expanded in vitro.

Tumor-draining lymph nodes (tumor-DLNs) provide a rich source of tumor-reactive lymphocytes which can be used in adoptive immunotherapy (AIT) and that circumvent the need to resect autologous tumor, without the challenges and shortcomings associated with using autologous tumor or anti-CD3 monoclonal antibody. Bryostatin/Ionomycin (Bryo/Io) provide a useful method of activating tumor-DLNs such that they can readily be expanded to sufficient numbers to be used in AIT, and growing the tumor-DLN lymphocytes in the gamma chain cytokines IL-7 plus IL-15 is superior to IL-2 in terms of T cell numbers and phenotype. AIT with these cells induces tumor regression and provides protection against metastases and future tumor challenge. Here, we provide a stepwise protocol to sensitize tumor-DLN cells in donor mice, activate tumor-DLN T cells ex vivo using Bryo/Io, expansion of these cells in gamma chain cytokines and adoptive transfer of the expanded cells back into tumor-bearing hosts. Methods relevant to these experiments, such as injecting tumor cells intravenously and monitoring for pulmonary metastases, tumor volume measurement and resection, and use of luciferase-expressing tumor cells to monitor for metastases following resection, are described in detail. The methods outlined herein can be easily adapted to suit similar experiments across multiple tumor cell lines and syngeneic mouse models.

Secreted factors induced by PKC modulators do not indirectly cause HIV latency reversal.

HIV can establish a long-lived latent infection in cells harboring integrated non-expressing proviruses. Latency reversing agents (LRAs), including protein kinase C (PKC) modulators, can induce expression of latent HIV, thereby reducing the latent reservoir in animal models. However, PKC modulators such as bryostatin-1 also cause cytokine upregulation in peripheral blood mononuclear cells (PBMCs), including cytokines that might independently reverse HIV latency. To determine whether cytokines induced by PKC modulators contribute to latency reversal, primary human PBMCs were treated with bryostatin-1 or the bryostatin analog SUW133, a superior LRA, and supernatant was collected. As anticipated, LRA-treated cell supernatant contained increased levels of cytokines compared to untreated cell supernatant. However, exposure of latently-infected cells with this supernatant did not result in latency reactivation. These results indicate that PKC modulators do not have significant indirect effects on HIV latency reversal in vitro and thus are targeted in their latency reversing ability.

Bryostatin-1: a promising compound for neurological disorders.

The central nervous system (CNS) is the most complex system in human body, and there is often a lack of effective treatment strategies for the disorders related with CNS. Natural compounds with multiple pharmacological activities may offer better options because they have broad cellular targets and potentially produce synergic and integrative effects. Bryostatin-1 is one of such promising compounds, a macrolide separated from marine invertebrates. Bryostatin-1 has been shown to produce various biological activities through binding with protein kinase C (PKC). In this review, we mainly summarize the pharmacological effects of bryostatin-1 in the treatment of multiple neurological diseases in preclinical studies and clinical trials. Bryostatin-1 is shown to have great therapeutic potential for Alzheimer's disease, multiple sclerosis, fragile X syndrome, stroke, traumatic brain injury, and depression. It exhibits significant rescuing effects on the deficits of spatial learning, cognitive function, memory and other neurological functions caused by diseases, producing good neuroprotective effects. The promising neuropharmacological activities of bryostatin-1 suggest that it is a potential candidate for the treatment of related neurological disorders although there are still some issues needed to be addressed before its application in clinic.

Computational insight into the binding of bryostatin 1 with ferritin: implication of natural compounds in Alzheimer's disease therapeutics.

Neuronal damage in iron-sensitive brain regions occurs as a result of iron dyshomeostasis. Increased iron levels and iron-related pathogenic triggers are associated with neurodegenerative diseases, including Alzheimer's disease (AD). Ferritin is a key player involved in iron homeostasis. Major pathological hallmarks of AD are amyloid plaques, neurofibrillary tangles (NFTs) and synaptic loss that lead to cognitive dysfunction and memory loss. Natural compounds persist in being the most excellent molecules in the area of drug discovery because of their different range of therapeutic applications. Bryostatins are naturally occurring macrocyclic lactones that can be implicated in AD therapeutics. Among them, Bryostatin 1 regulates protein kinase C, a crucial player in AD pathophysiology, thus highlighting the importance of bryostatin 1 in AD management. Thus, this study explores the binding mechanism of Bryotstain 1 with ferritin. In this work, the molecular docking calculations revealed that bryostatin 1 has an appreciable binding potential towards ferritin by forming stable hydrogen bonds (H-bonds). Molecular dynamics simulation studies deciphered the binding mechanism and conformational dynamics of ferrritin-bryostatin 1 system. The analyses of root mean square deviation, root mean square fluctuations, Rg, solvent accessible surface area, H-bonds and principal component analysis revealed the stability of the ferritin-bryostatin 1 docked complex throughout the trajectory of 100 ns. Moreover, the free energy landscape analysis advocated that the ferritin-bryostatin 1 complex stabilized to the global minimum. Altogether, the present work delineated the binding of bryostatin 1 with ferritin that can be implicated in the management of AD.Communicated by Ramaswamy H. Sarma.

Bryostatin-1 Attenuates Ischemia-Elicited Neutrophil Transmigration and Ameliorates Graft Injury after Kidney Transplantation.

Ischemia reperfusion injury (IRI) is a form of sterile inflammation whose severity determines short- and long-term graft fates in kidney transplantation. Neutrophils are now recognized as a key cell type mediating early graft injury, which activates further innate immune responses and intensifies acquired immunity and alloimmunity. Since the macrolide Bryostatin-1 has been shown to block neutrophil transmigration, we aimed to determine whether these findings could be translated to the field of kidney transplantation. To study the effects of Bryostatin-1 on ischemia-elicited neutrophil transmigration, an in vitro model of hypoxia and normoxia was equipped with human endothelial cells and neutrophils. To translate these findings, a porcine renal autotransplantation model with eight hours of reperfusion was used to study neutrophil infiltration in vivo. Graft-specific treatment using Bryostatin-1 (100 nM) was applied during static cold storage. Bryostatin-1 dose-dependently blocked neutrophil activation and transmigration over ischemically challenged endothelial cell monolayers. When applied to porcine renal autografts, Bryostatin-1 reduced neutrophil graft infiltration, attenuated histological and ultrastructural damage, and improved renal function. Our novel findings demonstrate that Bryostatin-1 is a promising pharmacological candidate for graft-specific treatment in kidney transplantation, as it provides protection by blocking neutrophil infiltration and attenuating functional graft injury.

Molecular dynamics simulation studies on binding of activator and inhibitor to Munc13-1 C1 in the presence of membrane.

Munc13-1 is a presynaptic active zone protein that plays a critical role in priming the synaptic vesicle and releasing neurotransmitters in the brain. Munc13-1 acts as a scaffold and is activated when diacylglycerol (DAG)/phorbol ester binds to its C1 domain in the plasma membrane. Our previous studies showed that bryostatin 1 activated the Munc13-1, but resveratrol inhibited the phorbol ester-induced Munc13-1 activity. To gain structural insights into the binding of the ligand into Munc13-1 C1 in the membrane, we conducted 1.0 µs molecular dynamics (MD) simulation on Munc13-1 C1-ligand-lipid ternary system using phorbol 13-acetate, bryostatin 1 and resveratrol as ligands. Munc13-1 C1 shows higher conformational stability and less mobility along membrane with phorbol 13-acetate and bryostatin 1 than with resveratrol. Bryostatin 1 and phorbol ester remained in the protein active site, but resveratrol moved out of Munc13-1 C1 during the MD simulation. While bryostatin 1-bound Munc13-1 C1 showed two different positioning in the membrane, phorbol 13-acetate and resveratrol-bound Munc13-1 C1 only showed one positioning. Phorbol 13-acetate formed hydrogen bond with Ala-574 and Gly-589. Bryostatin 1 had more hydrogen bonds with Trp-588 and Arg-592 than with other residues. Resveratrol formed hydrogen bond with Ile-590. This study suggests that different ligands control Munc13-1 C1's mobility and positioning in the membrane differently. Ligand also has a critical role in the interaction between Munc13-1 C1 and lipid membrane. Our results provide structural basis of the pharmacological activity of the ligands and highlight the importance of membrane in Munc13-1 activity.Communicated by Ramaswamy H. Sarma.

Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review.

Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well established, with the identification of key pharmacophoric features important for PKC modulation. The low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate the PKCα activity; however, the cyclic framework appears to be essential for the desired level of potency. Another simplified analog 17 ("picolog") exhibited potent and in-vivo efficacy against lymphoma. Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease. Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal effect as a single agent, however, provided encouraging results in combination with other chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to emerge as treatment for cancer along with many other diseases.

Bryostatin 1 Promotes Synaptogenesis and Reduces Dendritic Spine Density in Cortical Cultures through a PKC-Dependent Mechanism.

The marine natural product bryostatin 1 has demonstrated procognitive and antidepressant effects in animals and has been entered into human clinical trials for treating Alzheimer's disease (AD). The ability of bryostatin 1 to enhance learning and memory has largely been attributed to its effects on the structure and function of hippocampal neurons. However, relatively little is known about how bryostatin 1 influences the morphology of cortical neurons, key cells that also support learning and memory processes and are negatively impacted in AD. Here, we use a combination of carefully designed chemical probes and pharmacological inhibitors to establish that bryostatin 1 increases cortical synaptogenesis while decreasing dendritic spine density in a protein kinase C (PKC)-dependent manner. The effects of bryostatin 1 on cortical neurons are distinct from those induced by neural plasticity-promoting psychoplastogens such as ketamine. Compounds capable of increasing synaptic density with concomitant loss of immature dendritic spines may represent a unique pharmacological strategy for enhancing memory by improving signal-to-noise ratio in the central nervous system.

Neuro-regeneration Therapeutic for Alzheimer's Dementia: Perspectives on Neurotrophic Activity.

Alzheimer's disease (AD), the leading disorder of memory impairment in our aging population, is increasing at an alarming rate. AD is currently identified by three 'gold standard criteria': (i) dementia in life, (ii) amyloid plaques at autopsy, and (iii) neurofibrillary tangles at autopsy. Several autopsy studies have indicated that dementia in life is a consequence of lost synaptic networks in the brain, while many clinical trials targeting neurotoxic amyloid beta (Aß) have consistently failed to produce therapeutic effects on memory function in AD patients. Restoring cognitive function(s) by activating endogenous repairing/regenerating mechanisms that are synaptogenic and antiapoptotic (preventing neuronal death), however, is emerging as a necessary disease-modifying therapeutic strategy against AD and possibly for other degenerative dementias, such as Parkinson's disease and multi-infarct dementia.

Inhibition of Inflammation, Suppression of Matrix Metalloproteinases, Induction of Neurogenesis, and Antioxidant Property Make Bryostatin-1 a Therapeutic Choice for Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation and myelin damage. Pro-inflammatory cytokines, oxidative stress, high level of matrix metalloproteinases (MMPs) activity and blood-brain barrier (BBB) damage, immune-mediated destruction of myelin and neuron loss are involved in the pathogenesis of MS. The currently approved treatments for MS include injectable drugs (interferon-ß and glatiramer acetate), oral drugs (fingolimod), and monoclonal antibodies (natalizumab). The mentioned therapeutic choices are mostly focused on the inhibition of inflammation. Therefore, the search for a multi-target therapeutic choice remains unchallenged. It seems that a drug with anti-inflammatory, oxidative stress inhibitory, reduction of MMPs activity, and neurogenesis stimulatory properties may be effective for treatment of MS. In this regard, Bryostatin-1 as a macrolide and marine natural product has been selected as a therapeutic choice. Studies indicate that Bryostatin-1 has anti-inflammatory and antioxidant properties and decreases MMPs level and BBB damage. Furthermore, Bryostatin-1 has a neuroprotective effect and promotes neurogenesis and differentiation of oligodendrocyte progenitor stem cells as a critical step for remyelination/myelogenesis. Based on these properties, we hypothesized here that Bryostatin-1 is an effective treatment in MS.