Rock Creek Pharmaceuticals Inc. (fka RCPIQ)

[Buddhahead]

If you Google Wikipedia for 'Microglia', you'll find an interesting discourse as applied to AD:

http://en.wikipedia.org/wiki/Microglia

Excerpts:
"Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system (CNS).
Microglia constitute 10-15% of all cells found within the brain.[1] Microglia (and astrocytes) are distributed in large non-overlapping regions throughout the brain and spinal cord.[2][3] Microglia are constantly scavenging the CNS for plaques, damaged neurons and infectious agents.[4] The brain and spinal cord are considered "immune privileged" organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood–brain barrier, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood–brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (few antibodies are small enough to cross the blood brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS.[5] They achieve this sensitivity in part by having unique potassium channels that respond to even small changes in extracellular potassium.[4]"

"Role in chronic neuroinflammation[edit]
The word neuroinflammation has come to stand for chronic, central nervous system (CNS) specific, inflammation-like glial responses that may produce neurodegenerative symptoms such as plaque formation, dystrophic neurite growth, and excessive tau phosphorylation.[16] It is important to distinguish between acute and chronic neuroinflammation. Acute neuroinflammation is generally caused by some neuronal injury after which microglia migrate to the injured site engulfing dead cells and debris.[16] The term neuroinflammation generally refers to more chronic, sustained injury when the responses of microglial cells contribute to and expand the neurodestructive effects, worsening the disease process.[16]
When microglia are activated they take on an amoeboid shape and they alter their gene expression. Altered gene expression leads to the production of numerous potentially neurotoxic mediators. These mediators are important in the normal functions of microglia and their production is usually decreased once their task is complete.[17] In chronic neuroinflammation, microglia remain activated for an extended period during which the production of mediators is sustained longer than usual.[17] This increase in mediators contributes to neuronal death.[17]
Neuroinflammation is distinct from inflammation in other organs, but does include some similar mechanisms such as the localized production of chemoattractant molecules to the site of inflammation.[17] The following list contains a few of the numerous substances that are secreted when microglia are activated:
Cytokines[edit]
Microglia activate the proinflammatory cytokines IL-1a, IL-1ß and TNF-a in the CNS.[17] Cytokines play a potential role in neurodegeneration when microglia remain in a sustained activated state.[17] Direct injection of the cytokines IL-1a, IL-1ß and TNF-a into the CNS result in local inflammatory responses and neuronal degradation.[17] This is in contrast with the potential neurotrophic (inducing growth of neurons) actions of these cytokines during acute neuroinflammation.[17]
Chemokines[edit]
Chemokines are cytokines that stimulate directional migration of inflammatory cells in vitro and in vivo.[17] Chemokines are divided into four main subfamilies: C, CC, CXC, and CX3C. Microglial cells are sources of some chemokines and express the monocyte chemoattractant protein-1 (MCP-1) chemokine in particular.[17] Other inflammatory cytokines like IL-1ß and TNF-a, as well as bacterial-derived lipopolysaccharide (LPS) may stimulate microglia to produce MCP-1, MIP-1a, and MIP-1ß.[17] Microglia can express CCR3, CCR5, CXCR4, and CX3CR1 in vitro.[17] Chemokines are proinflammatory and therefore contribute to the neuroinflammation process.[17]
Proteases[edit]
When microglia are activated they induce the synthesis and secretion of proteolytic enzymes that are potentially involved in many functions.[17] There are a number of proteases that possess the potential to degrade both the extracellular matrix and neuronal cells that are in the neighborhood of the microglia releasing these compounds.[17] These proteases include; cathepsins B, L, and S, the matrix metalloproteinases MMP-1, MMP-2, MMP-3, and MMP-9, and the metalloprotease-disintegrin ADAM8 (plasminogen) which forms outside microglia and degrades the extracellular matrix.[17] Both Cathepsin B, MMP-1 and MMP-3 have been found to be increased in Alzheimer's disease (AD) and cathepsin B is increased in multiple sclerosis (MS).[17] Elastase, another protease, could have large negative effects on the extracellular matrix.[17]
Amyloid precursor protein[edit]
Microglia synthesize amyloid precursor protein (APP) in response to excitotoxic injury.[17] Plaques result from abnormal proteolytic cleavage of membrane bound APP.[17] Amyloid plaques can stimulate microglia to produce neurotoxic compounds such as cytokines, excitotoxin, nitric oxide and lipophylic amines, which all cause neural damage.[18] Plaques in Alzheimer's disease contain activated microglia.[17] A study has shown that direct injection of amyloid into brain tissue activates microglia, which reduces the number of neurons.[18] Microglia have also been suggested as a possible source of secreted ß amyloid.[17]"

"Role of microglia in neurodegeneration[edit]
Neurodegenerative disorders are characterized by progressive cell loss in specific neuronal populations.[17] "Many of the normal trophic functions of glia may be lost or overwhelmed when the cells become chronically activated in progressive neurodegenerative disorders, for there is abundant evidence that in such disorders, activated glia play destructive roles by direct and indirect inflammatory attack."[17] The following are prominent examples of microglial cells' role in neurodegenerative disorders.
Alzheimer's disease[edit]
Alzheimer's disease (AD) is a progressive, neurodegenerative disease where the brain develops abnormal clumps (amyloid plaques) and tangled fiber bundles (neurofibrillary tangles).[20]
There are many activated microglia over-expressing IL-1 in the brains of Alzheimer patients that are distributed with both Aß plaques and neurofibrillary tangles.[19] This over expression of IL-1 leads to excessive tau phosphorylation that is related to tangle development in Alzheimer's disease.[19]
Many activated microglia are found to be associated with amyloid deposits in the brains of Alzheimer's patients.[17] Microglia interact with ß-amyloid plaques through cell surface receptors that are linked to tyrosine kinase based signaling cascades that induce inflammation.[17] When microglia interact with the deposited fibrillar forms of ß-amyloid it leads to the conversion of the microglia into an activated cell and results in the synthesis and secretion of cytokines and other proteins that are neurotoxic.[17]
One preliminary model as to how this would occur involves a positive feedback loop. When activated, microglia will secrete proteases, cytokines, and reactive oxygen species. The cytokines may induce neighboring cells to synthesize amyloid precursor protein. The proteases then possibly could cause the cleaving required to turn precursor molecules into the beta amyloid that characterizes the disease. Then, the oxygen species encourage the aggregation of beta amyloid in order to form plaques. The growing size of these plaques then in turn triggers the action of even more microglia, which then secrete more cytokines, proteases, and oxygen species, thus amplifying the neurodegeneration.[21]
Treatment[edit]
Non-steroidal anti-inflammatory drugs (NSAIDs) have proven to be effective in reducing the risk of AD.[17] "Sustained treatment with NSAIDs lowers the risk of AD by 55%, delays disease onset, attenuates symptomatic severity and slows the loss of cognitive abilities. The main cellular target for NSAIDs is thought to be microglia. This is supported by the fact that in patients taking NSAIDs the number of activated microglia is decreased by 65%."[17]
Parkinson's disease[edit]
Parkinson's disease is a movement disorder in which the dopamine-producing neurons in the brain do not function as they should, the neurons of the Substantia Nigra become dysfunctional and eventually die, leaving a lack of dopamine input into the striatum. This causes the symptoms of Parkinson's disease.[22]
Cardiovascular Diseases[edit]
Recently microglial activation has been reported in rats with myocardial infarction (Rana et al.,2010). This activation was specific to brain nuclei involved in cardiovascular regulation suggesting possible role of microglial activation in pathogenesis of heart failure."

"As a target to treat neuroinflammation[edit]
Inhibition of activation[edit]
One way to control neuroinflammation is to inhibit microglial activation. Studies on microglia have shown that they are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (MAPK).[17] Previous approaches to down-regulate activated microglia focused on immunosuppressants.[17] Recently, minocycline (a tetracycline derivative) has shown down-regulation of microglial MAPK.[17] Another promising treatment is CPI-1189, which induces cell death in a TNF a-inhibiting compound that also down-regulates MAPK.[17] Recent study shows that nicergoline (Sermion) suppresses the production of proinflammatory cytokines and superoxide anion by activated microglia.[39] Microglial activation can be inhibited by MIF (microglia/macrophage inhibitory factor, tuftsin fragment 1–3, Thr-Lys-Pro). MIF-treated mice showed reduced brain injury and improved neurologic function in a mouse model of collagenase-induced intracerebral hemorrhage.[40][41

Regulation of chemokine receptor[edit]
The chemokine receptor, CX3CR1, is expressed by microglia in the central nervous system.[42] Fractalkine (CX3CL1) is the exclusive ligand for CX3CR1 and is made as a transmembrane glycoprotein from which a chemokine can be released.[42] Cardona, et al. stated in 2006 that "using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity."[42] Further studies into how CX3CR1 regulates microglial neurotoxicity could lead to new therapeutic strategies for neuroprotection.[42]
Inhibition of amyloid deposition[edit]
Inhibitors of amyloid deposition include the enzymes responsible for the production of extracellular amyloid such as ß-secretase and ?-secretase inhibitors.[17] Currently the ?-secretase inhibitors are in phase II clinical trials as a treatment for Alzheimer's disease but they have immunosuppressive properties, which could limit their use.[17] Another strategy involves increasing the antibodies against a fragment of amyloid.[17] This treatment is also in phase II clinical trials for the treatment of Alzheimer's disease.[17]
Inhibition of cytokine synthesis[edit]
Glucocorticosteroids (GCS) are anti-inflammatory steroids that inhibit both central and peripheral cytokine synthesis and action.[17] In a study conducted by Kalipada Pahan from the Department of Pediatrics at the Medical University of South Carolina, both lovastatin and sodium phenylacetate were found to inhibit TNF-a, IL-1ß, and IL-6 in rat microglia.[43] This shows that the mevalonate pathway plays a role in controlling the expression of cytokines in microglia and may be important in developing drugs to treat neurodegenerative diseases.[43] Naltrexone may provide a solution to the inflammatory mediators produced by microglia. Although naltrexone's main action is to competitively bind to opioid receptors, new research shows that naltrexone, when given in low doses once per day (low-dose naltrexone), can inhibit cytokine synthesis by microglia cells. This mechanism is still being investigated, but there are already studies that indicate that it helps some patients suffering from fibromyalgia syndrome. Naltrexone shows more promise than GCSs because the GCSs inhibit immune system function more generally, increase allergic reactions and, as the name implies, increase blood glucose levels.[44][45]"



From the RCPI Website:
"EUROPEAN JOURNAL OF PHARMACOLOGY Volume 670, Issues 2–3, November 30, 2011, Pages 384–391

Abstract:
Brain Aß accumulation represents a key pathological hallmark in Alzheimer's disease. In this study, we investigated the impact of anatabine, a minor alkaloid present in plants of the Solanacea family on Aß production in vitro using a cell line overexpressing the human amyloid precursor protein (APP) and in vivo using a transgenic mouse model of Alzheimer's disease. In vitro, anatabine lowers Aß1–40 and Aß1–42 levels in a dose dependent manner and reduces sAPPß production without impacting sAPPa levels suggesting that anatabine lowers Aß production by mainly impacting the ß-cleavage of APP. Additionally, we show that anatabine lowers NF?B activation at doses that inhibit Aß production in vitro. Since NF?B is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Aß production), we determined the impact of anatabine on BACE-1 transcription. We show that anatabine inhibits BACE-1 transcription and reduces BACE-1 protein levels in human neuronal like SHSY-5Y cells suggesting that the Aß lowering properties of anatabine are mediated via a regulation of BACE-1 expression. In vivo, we show that an acute treatment with anatabine for four days significantly lowers brain soluble Aß1–40 and Aß1–42 levels in a transgenic mouse model of Alzheimer's disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain Aß accumulation."

Article at:
http://rockcreekpharmaceuticals.com/html/article_5.php