Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive neuron loses in memoryrelated brain structures. Five drugs have been approved by the FDA to treat Alzheimer’s disease; however, these drugs have failed to modify or significantly slow disease progression. New therapies are needed to delay the course of this disease and hopefully prevent further neuron losses. This review describes available AD drugs and several novel approaches presently being investigated. We next describe relevant biomarkers and urge greater research interest in the potential utilization of neurotrophic agents to treat AD. Neurotrophins such as nerve growth factor, brain-derived neurotrophic factor and hepatocyte growth factor (HGF) are capable of stimulating dendritic arborization, synaptogenesis, stem cell differentiation, neurogenesis, and decreases in neuroinflammation, oxidative stress-induced damage and neurotoxicity due to a wide range of cellular insults. We present the strategy of utilizing small molecule analogs specifically designed to penetrate the blood-brain barrier and facilitate dimerization and activation of the HGF/Met receptor system. These molecules have been shown to encourage the formation of new functional synaptic connections, induce long-term potentiation and augment memory consolidation and retrieval in animal models of AD. Such molecules may be appropriate for use at the first indication of mild cognitive impairment, and perhaps prophylactically in those individuals who are most likely to develop dementia due to genetic, health, behavioral and life-style predisposing factors.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive neuron losses in memory-associated brain structures that rob patients of their dignity and quality of life. Five drugs have been approved by the FDA to treat AD but none modify or significantly slow disease progression. New therapies are needed to delay the course of this disease with the ultimate goal of preventing neuron losses and preserving memory functioning. In this review we describe the renin-angiotensin II (AngII) system (RAS) with specific regard to its deleterious contributions to hypertension, facilitation of neuroinflammation and oxidative stress, reduced cerebral blood flow, tissue remodeling, and disruption of memory consolidation and retrieval. There is evidence that components of the RAS, AngIV and Ang(1-7), are positioned to counter such damaging influences and these systems are detailed with the goal of drawing attention to their importance as drug development targets. Ang(1-7) binds at the Mas receptor, while AngIV binds at the AT4 receptor subtype, and these receptor numbers are significantly decreased in AD patients, accompanied by declines in brain aminopeptidases A and N, enzymes essential for the synthesis of AngIV. Potent analogs may be useful to counter these changes and facilitate neuronal functioning and reduce apoptosis in memory associated brain structures of AD patients.

Alzheimer’s disease (AD) patients are presently without adequate treatment thus new therapeutic approaches are needed to slow and hopefully reverse disease progression. Neurotrophic agents such as nerve growth factor and brain-derived neurotrophic factor have received research attention concerning their potential to treat AD but have not progressed to clinical trials due to their large size, inability to penetrate the blood-brain barrier (BBB), and the high cost of synthesis. This review focuses on one over looked neurotrophin, hepatocyte growth factor (HGF) that acts via the Type 1 tyrosine kinase receptor Met to mediate stem cell differentiation, synaptogenesis, neurogenesis, and protect against tissue insults in a wide range of cell types including neurons. We have determined that the brain angiotensin and HGF/c-Met systems interact in such a way that angiotensin IV (AngIV)-based analogs including Nle1-AngIV, Norleual-AngIV, Dihexa, and others influence HGF dimerization which is a prerequisite to binding at the Met receptor. Several of these analogs have shown the ability to facilitate the formation of new functional synaptic connections in hippocampal slices, promote neurogenesis, and augment memory consolidation and retrieval in animal models of AD. This family of compounds represents a new class of drugs with lead candidates that are orally active, penetrate the BBB sufficiently to reach therapeutic concentrations, and reverse memory deficits seen in animal models of dementia.

Major depression is a common form of mental disorder affecting approximately 15% of the population at least once during lifetime. The etiology of depression is complex with potential contributions from central and peripheral systemic factors, and several CNS impacting diseases. Presently employed antidepressant medications are poorly responded to by upwards of 50% of patients and typically require weeks of treatment to be effective. Recent post-mortem brain scans indicate significant volume reductions in two limbic brain structures, the hippocampus and prefrontal cortex of depressed patients. These findings focus attention on hippocampal plasticity in the neuropathology of depression and the possible dysfunction of several important processes including neurogenesis, synaptogenesis, and contributions by neurotrophic growth factors. The hepatocyte growth factor (HGF)/c-Met receptor system is a powerful mediator of synaptogenesis and neurogenesis, and if adequately activated may serve to counter the neuropathology of depression. The brain renin-angiotensin system (RAS) interacts with the HGF/c-Met system and plays a major role in responding to stress and the pathophysiology of depression. We have developed an angiotensin IV-based small molecule designed to activate the HGF/c-Met receptor system in order to provide neuroprotection, synaptogenesis, and neurogenesis in the hippocampus and prefrontal cortex. This analog may be efficacious in treating the neuropathology of depression.

Alzheimer's disease (AD) is a progressive neurodegenerative disease increasing in frequency as life expectancy of the world's population increases. There are an estimated 5 million diagnosed AD patients in the U.S. and 16 million worldwide with no adequate treatment presently available. New therapeutic approaches are needed to slow, and hopefully reverse, disease progression. This review summarizes available information regarding an overlooked therapeutic target that may offer a treatment to slow and hopefully halt AD, namely the hepatocyte growth factor (HGF)/c-Met receptor system. Activation of the c-Met receptor stimulates mitogenesis, motogenesis, morphogenesis, the ability to mediate stem cell differentiation and neurogenesis, and protects against tissue insults in a wide range of cells including neurons. This growth factor system has recently been shown to induce dendritic arborization and synaptogenesis when stimulated by a newly developed angiotensin-based analogue, N-hexanoic-Tyr-Ile-(6) amino hexanoic amide (Dihexa). This small molecule was derived from the pre-prototype molecule Nle1-angiotensin IV and has shown promise in facilitating the formation of new functional synaptic connections and augmenting memory consolidation in animal models of AD. Dihexa is a first-in-class compound that is orally active, penetrates the blood-brain barrier, and facilitates memory consolidation and retrieval. This angiotensin-based small molecule may be efficacious as a treatment for AD.

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The classic renin-angiotensin system (RAS) is described as a circulating hormone system with primary roles in the regulation of blood pressure, body water balance and thirst and control over vasopressin and aldosterone release. Recently local tissue RASs have been identified with regulatory physiological functions and also with pathophysiological processes including fibrosis, inflammation and dysfunctional cell proliferation. There is a strong correlation between organs vulnerable to diabetic–induced hyperglycemic injury (eg. kidney and retina) and the over activation of local RASs. Increased angiotensin II concentrations in these tissues promotes hypertension and end-organ damage in at least two ways: 1) By activating AT 1 receptor proteins thus inducing changes in local blood flow and tissue hydration and 2) Exacerbating hyperglycemic-induced oxidative stress, elevated polyol and hexosamine pathway variability and facilitating glycation end-products. Thus, inhibition of the RAS has become an important treatment approach to control diabetic related hypertension, nephropathy and to a lesser extent retinopathy. The present review emphasizes the recently established importance of the hepatocyte growth factor (HGF)/c-Met receptor system interacting with the RAS in Type 2 diabetes and their likely contribution to end-organ damage. A hypothesis is offered concerning how the pancreatic RAS may affect dimerization of HGF and in turn activation of the c-Met receptor to promote β cell proliferation and insulin synthesis. We conclude with details concerning the

A subset of angiotensin IV (AngIV)-related molecules are known to possess procognitive/antidementia properties and have been considered as templates for potential therapeutics. However, this potential has not been realized because of two factors: 1) a lack of blood-brain barrier-penetrant analogs, and 2) the absence of a validated mechanism of action. The pharmacokinetic barrier has recently been overcome with the synthesis of the orally active, blood-brain barrier-permeable analog N-hexanoic-tyrosine-isoleucine-(6) aminohexanoic amide (dihexa). Therefore, the goal of this study was to elucidate the mechanism that underlies dihexa's procognitive activity. Here, we demonstrate that dihexa binds with high affinity to hepatocyte growth factor (HGF) and both dihexa and its parent compound Norleucine 1-AngIV (Nle(1)-AngIV) induce c-Met phosphorylation in the presence of subthreshold concentrations of HGF and augment HGF-dependent cell scattering. Further, dihexa and Nle(1)-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself. These actions were inhibited by an HGF antagonist and a short hairpin RNA directed at c-Met. Most importantly, the procognitive/antidementia capacity of orally delivered dihexa was blocked by an HGF antagonist delivered intracerebroventricularly as measured using the Morris water maze task of spatial learning.

The brain renin-angiotensin system (RAS) has available the necessary functional components to produce the active ligands angiotensins II, III, IV, angiotensin (1-7), and angiotensin (3-7). These ligands interact with several receptor proteins including AT1, AT2, AT4 and Mas distributed within the central and peripheral nervous systems as well as local RASs in several organs. This review first describes the enzymatic pathways in place to synthesize these ligands and the binding characteristics of these angiotensin receptor subtypes. We next discuss current hypotheses to explain the disorders of Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as research efforts focused on the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), in their treatment. ACE inhibitors and ARBs are showing promise in the treatment of several neurodegenerative pathologies; however, there is a need for the development of analogues capable of penetrating the blood-brain barrier and acting as agonists or antagonists at these receptor sites. Angiotensins II (AngII) and IV (Ang(IV) have been shown to play opposing roles regarding memory acquisition and consolidation in animal models. We discuss the development of efficacious AngIV analogues in the treatment of animal models of AD and PD. These AngIV analogues act via the AT4 receptor subtype which may coincide with the hepatocyte growth factor (HGF)/c-Met receptor system. Finally, future research directions are described concerning new approaches to the treatment of these two neurological diseases.

Reconfiguration of extracellular matrix proteins appears to be necessary for the synaptic plasticity that underlies memory consolidation. The primary candidates involved in controlling this process are a family of endopeptidases called matrix metalloproteinases (MMPs); however, the potential role of MMPs in nicotine addiction-related memories has not been adequately tested. Present results indicate transient changes in hippocampal MMP-2, -3, and -9 expression following context dependent learning of nicotine-induced conditioned place preference (CPP). Members of a CPP procedural control group also indicated similar MMP changes, suggesting that memory activation occurred in these animals as well. However, hippocampal MMP-9 expression was differentially elevated in members of the nicotine-induced CPP group on days 4 and 5 of training. Inhibition of MMPs using a broad spectrum MMP inhibitor (FN439) during nicotine-induced CPP training blocked the acquisition of CPP. Elevations in hippocampal and prefrontal cortex MMP-3 expression-but not MMP-2 and -9-accompanied reactivation of a previously learned drug related memory. Decreases in the actin regulatory cytoskeletal protein cortactin were measured in the HIP and PFC during the initial two days of acquisition of CPP; however, no changes were seen following re-exposure to the drug related environment. These results suggest that MMP-9 may be involved in facilitating the intracellular and extracellular events required for the synaptic plasticity underlying the acquisition of nicotine-induced CPP. Furthermore, MMP-3 appears to be important during re-exposure to the drug associated environment. However, rats introduced into the CPP apparatus and given injections of vehicle rather than nicotine during training also revealed a pattern of MMP expression similar to nicotine-induced CPP animals.

Background: Recent changes to the CRT guidelines recommend BVICDs should be implanted in patients with less advanced heart failure. The cost effectiveness of CRT depends very much on battery longevity. In patients with less advanced heart failure and an overall better prognosis, battery longevity will become increasingly important in maintaining cost effectiveness. Aim: To compare battery longevity between two major manufacturers Methods: The time to elective replacement of BVICDs implanted at a single institution from 2004 was reviewed Results: 301 BVICDs were implanted in 264 patients. The median age was 66 years. The median EF was 25%. 142 Guidant and 159 Medtronic devices were implanted during the period. All devices included in this analysis had a functioning LV lead implanted and programmed to pace both ventricles. The estimated mean time to ERI for all devices was 2089 days. The estimated mean time to replacement for Guidant devices was 2170 days compared to Medtronic 1840 days (see Fig. 1). This difference was significant (p = 0.024). The median LV pacing threshold of all leads was 1 [email protected] ms. 30 LV (10%) leads had a high pacing (>2.5 V) thresholds. There was no difference between manufacturers. During a median follow up of 987 days, 36 patients died. Conclusions: The estimated median time to device replacement was a modest 2089 days. A significant difference between manufactures was observed. Further advances in battery technology that allow greater longevity is urgently required if cost effectiveness of CRT is to be maintained as we move to a lower risk patient group.