Intracranial administration of vaccinia virus complement control protein in Mo/Hu APPswe PS1dE9 transgenic mice at an early age shows enhanced performance at a later age using a cheese board maze test.

One of the key pro-inflammatory mediators activated by amyloid protein in neurodegenerative disorders of the brain, such as Alzheimer's disease is the complement system. Vaccinia virus complement control protein secreted by vaccinia virus, commonly known as VCP, was found to inhibit amyloid protein mediated up-regulation of complement system in vitro. In the current research investigation, VCP was administered twice (First dose at 3 weeks and the second dose at 6-7 months) intracranially into the parietal cortical area of Mo/Hu APPswe transgenic mice. At the age of 2 years or more, the same mice were subjected to cued-learning, spatial learning, probe and reverse probe trial paradigms of cheese board maze tasks for cognitive assessment. A significant difference was observed between VCP treated mice and the transgenic controls on days two and three of the cued trials and probe trials. The VCP treated group showed a similar trend as revealed during the spatial learning trial and reverse probe trial. A differential pattern of thioflavine S staining was observed in the VCP treated group. These results suggest that administration of VCP at an early age in transgenic mice may be effective in regulating the progression to the familial form of Alzheimer's disease at a later age.

Early detection of memory deficits and memory improvement with vaccinia virus complement control protein in an Alzheimer's disease model.

Vaccinia virus complement control protein (VCP) inhibits both the classical and alternate complement pathways. In diseases such as traumatic brain injury (TBI) and Alzheimer's disease (AD), pathological inflammation is caused by amongst several factors, prolonged or inappropriate activation of the complement system and is a significant cause of neurodegeneration. This study investigates for the first time the use of a cheeseboard maze to evaluate cognitive deficits and the effect of VCP on memory processes in 2- and 3-month-old mice that express mutant amyloid precursor protein (APPswe) and mutant presenilin 1 (Ps1dE9) that correspond to a form of early onset AD. A four-phase training schedule was carried out on the cheeseboard maze before intracranial injections of 5 microl of VCP (1.7 microg/microl) or 5 microl saline. Two weeks later the effect of VCP on memory was evaluated. A statistically significant decrease in goal latency in VCP-treated mice than saline-treated transgenic mice in both the first probe and reverse tasks was observed. Similarly, after a second intracranial VCP or saline injection performed 2 months later, the 6.5- and 7.5-month aged VCP-injected mice performed significantly better in goal latency in both second probe and reverse tasks than saline-treated mice. These data also demonstrated that the use of a dry maze is a sensitive technique for distinguishing cognitive measures between non-transgenic and APPswe/PS1De9 transgenic mice at a much earlier stage.

Emerging anxiolytics.

Anxiety disorders are the most common of the psychiatric disorders and are also associated with significant economic costs and impaired work productivity. The first-line pharmacotherapy of pharmatherapy for a number of anxiety disorders comprises selective serotonin re-uptake inhibitors (SSRIs) and serotonin and noradrenaline re-uptake inhibitors (SNRIs). Benzodiazepines are still widely used for the treatment of several anxiety disorders. Although these agents are effective, many patients are treatment-refractory and more effective, better tolerated medications are required. This paper discusses the understandings of mechanisms involved in the anxiety disorders and reviews emerging medications. Mechanisms underlying the use of d-cycloserine, second generation antipsychotics and beta-blockers are particularly exciting.

Vaccinia virus complement control protein significantly improves sensorimotor function recovery after severe head trauma.

Vaccinia virus complement control protein (VCP) is an immunomodulator that inhibits both the classical and alternate pathways of the complement system, therefore preventing cell death and inflammation. VCP has previously been shown to be therapeutically effective in mild and moderate traumatic brain injury models. In this study the efficacy of VCP in a severe head injury model is investigated in Wistar rats. Training in a Morris Water Maze (MWM) commenced 2 days prior stereotaxic surgery. Rats were anesthetized before being subjected to a severe (2.7-3.0 atm) lateral fluid percussion injury (FPI) 3.0 mm lateral to the sagittal suture and 4.5 mm posterior to bregma. Ten microliters of VCP (1.7 microg/microl) was injected into the injury site immediately after FPI. Fourteen days post-FPI, rats were tested for spatial learning and memory using the Morris Water Maze, followed by a battery of sensorimotor tests. The latter tests showed statistically significant differences between saline-treated and VCP-treated rats in lateral left pulsion (p=0.001) and tactile placing (p=0.002) on the first 5 days of testing. In addition, significant differences in right lateral pulsion in the first 4 days (p=0.007) of testing was evident. The results suggest that in a severe head injury model, VCP at this dosage favorably influences sensorimotor outcome.

Administration of vaccinia virus complement control protein shows significant cognitive improvement in a mild injury model.

Previous studies have shown that traumatic mild brain injury in a rat model is accompanied by breakdown of the blood brain barrier and the accumulation of inflammatory cells. A therapeutic agent, vaccinia virus complement control protein (VCP), inhibits both the classic and the alternative pathways of the complement system and, in so doing, prevents cell death and inflammation. With the use of a rat mild injury model, the effects of VCP on spatial learning and memory were tested. Training in a Morris water maze consisted of a total of 16 trials over a 2-day period before rats were anesthetized and subjected to mild (1.0-1.1 atm) lateral fluid percussion injury (FPI) 3.0 mm lateral to the sagittal suture and 4.5 mm posterior to bregma. Ten microl of VCP (1.7 mg/ml) was injected into the injury site immediately after FPI. Two weeks post-FPI the rats were assessed in the Morris water maze for spatial learning and memory. Neurologic motor function tests were carried out after FPI for 14 consecutive days and again after 28 days. The Morris water maze data show that FPI plus saline-injected rats spent a significantly (P <0.05) larger amount of time in one of the incorrect quadrants than did the FPI plus VCP-injected group. Neurologic evaluations 24 hours postinjury revealed differences in sensorimotor function between groups. The results suggest that in a mild injury model, VCP influences neurologic outcome and offers some enhancement in spatial memory and learning.

Molecular mechanisms, emerging etiological insights and models to test potential therapeutic interventions in Alzheimer's disease.

Alzheimer's disease (AD) is a common cause of dementia, resulting from accumulated beta-amyloid protein deposits in the brain. As the population ages the incidence of AD is also on the rise. The incidence is very high in the developed countries where life expectancy is high, but it is also rising rapidly in the developing countries. Caring for patients suffering from AD is a major economic burden. The mechanisms underlying the neuropathology of AD are slowly being unravelled. Here we explore the many models and theories, which have been proposed over the years. We then discuss a potential therapeutic agent, vaccinia virus complement control protein (VCP), involved in modulating the complement system in AD. VCP has been shown in in vitro studies to block the complement activation caused by the beta peptide. Traumatic injuries to the brain are well known risk factors associated with the development of AD. VCP can also enhance functional recovery resulting from traumatic brain injury and may be able to slow the progression of traumatic brain injury to AD. Here we describe strategies for testing this hypothesis and evaluating other agents such as VCP.