Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 3, Issue 2, 2003

Scrapie is a slowly developing transmissible spongiform encephalopathy (TSE) occurring naturally in sheep and goats. At present, there is no efficient antemortem diagnostic test for TSEs. Electroencephalograms (EEGs), electrocardiograms (ECGs), magnetic-resonance imaging (MRI), positron emission tomography (PET), single photo emission computed tomography (SPECT), as well as conformation-dependent immunoassay (CDI), which show patterns characteristic of prion diseases, can obtain diagnostic information for TSEs. Other methods include testing cerebrospinal fluid for the presence of 14-3-3 proteins, Fourier transformation infrared spectroscopy (FTIR), brain biopsy, nasal biopsy and tonsil biopsy. For better TSE diagnosis, most TSEs need to be confirmed by the presentation of abnormal prion protein by Western blot, ELISA immunochemical methods, or immunocytochemistry methods, or by bioassays, a more sensitive but time-consuming method, which involves inoculating suspended homogenates into susceptible hosts and waiting for a long incubation period to conclude. An antemortem diagnostic test for TSEs can be done from spleen or lymph node biopsy by evaluating PrPSc presence. Since it has been suggested that the buffy coat of TSE animals may carry infectivity, a method for presymptomatic diagnosis of TSE from blood is clearly possible and desirable. At present, antibodies against prion protein cannot distinguish normal prion protein (PrP C) and abnormal prion protein (PrPSc); there is no reliable antibody to detect PrPSc only. In this review, we propose that the development of gene chips and / or protein chips for assays of TSE diseases might prove very useful. A great deal of basic research on TSE diagnosis, prevention, and treatment remains to be conducted.

Currently there is no effective treatment or prophylaxis against prion diseases. Although sporadic forms of this disease are relatively rare, the incidence of the transmissible prionoses is rising as a result of the exposure of Western European populations to bovine spongiform encephalopathy. It has been recently demonstrated in animal models that active or passive immunization may delay the onset of disease or even protect from the occurrence of symptoms if started prior to prion replication involving the central nervous system. Results of these animal studies suggest that development a vaccination approach for humans is feasible within the near future. Another aspect of prion diseases, potentially limiting the practical use of the vaccine, is lack of diagnostic tests detecting infected, non-symptomatic subjects. This can partially be overcome using high field magnetic resonance imaging (MRI), which in animal models is capable of detecting signal alterations in the brain before the onset of symptoms. Another potential way to improve the sensitivity and specificity for prion infection diagnosis is using ligands specifically targeting the β-sheet structure of PrPSc or anti-PrP antibodies. These can be coupled either with paramagnetic agents or radioisotopes making PrPSc detectable using MRI or scintigraphy respectively. Successful development of such ligands has been demonstrated for Alzheimer's disease and is currently being studied for prionoses.

The transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative disorders that affect a variety of mammalian species. These diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in elk and deer, and Creutzfeldt-Jakob disease (CJD) in humans. Recently, the transmission of BSE to humans has led to the formation of a new class of human TSE known as new variant CJD (nvCJD). Indicative of TSEs in vivo is the presence of an abnormal conformer of the naturally occurring host protein PrPC, referred to as PrPSc. Expression of PrPC by a potential host is an absolute requirement for a TSE infection to progress to clinical disease. While TSE agents ultimately affect the brain, for optimal pathogenesis and neuroinvasion kinetics most strains require functionally intact lymphoid organs. Accordingly, a majority of the data compiled to date on TSEs indicates that bolstering lymphoreticular function potentiates the ability of most agent strains to induce symptomatology in a given host. Attenuation of such functioning by various means, conversely, can severely diminish or, for some strains of agent, completely ablate pathogenesis and neuroinvasion. In this review we examine the cellular and physiological bases for these findings and explore possible underlying mechanisms of TSE pathogenesis. In addition, we examine new lines of research required to complete the puzzle of how TSEs utilize cells of the lymphoreticular system to their advantage and complete the neuroinvasion process.

Prion diseases are rare fatal neurodegenerative diseases of humans and other animals. The hallmark pathological features of TSEs are the spongiform degeneration of the brain, extensive neuronal loss, astrogliosis, and accumulation in the brain of a misfolded form of the prion protein (PrP). It has been proposed that PrP conformational changes may lead to the loss of physiological function of PrP or to acquisition of a neurotoxic activity by the misfolded protein, which may promote directly neuronal dysfunction. Alternatively, misfolded and aggregated prion protein may cause disease by inducing a chronic inflammatory reaction in the brain, leading to extensive brain damage mediated by reactive astrocytes and activated microglia. The aim of this article will be to review the different mechanisms that could relate PrP misfolding with brain degeneration and the emergence of TSE.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative disorders in humans and animals, and include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. All forms of prion diseases have common features: spongiform degeneration of the central nervous system, reactive gliosis, neuronal loss and in some cases, formation of amyloid plaques. Conversion of the host cellular prion protein (PrPC) into an abnormal, protease-resistant and infectious isoform (PrPSc) is believed to be a central molecular basis of neurodegeneration in prion diseases. Although there are vigorous disputes about the conversion mechanisms of PrPC to PrPSc, considerable evidence suggests that various factors such as molecular chaperones and transition metals may be closely associated with the PrP conversion process and that disturbance in the homeostasis of several transition metals may play an important role in the pathogenic mechanisms of prion diseases. Here, we briefly review and discuss current topics about the effects of transition metals in the PrP conversion mechanisms and in the pathogenesis of prion diseases.

We have recently observed a link between gender and the species barrier in the transmission of TSEs to mice. Gender effects are also observed in other age dependent neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), which may suggest the identity of common pathogenic pathways. While these effects could be caused by several factors, the most obvious explanation is that they are mediated by gender-specific hormonal influences.This review covers host factors that influence the transmission of TSEs as they relate to gender. The relationship between the phenomenology of prion disorders and other neurodegenerative diseases is discussed, which anticipates a role for sex steroid hormones in the control of the mechanisms of neurodegeneration.

Transmissible spongiform encephalopathies (TSEs) are an intriguing group of diseases that are a challenge to rational drug design for treatment or prevention by medicinal chemists and pharmacologists. There are similarities between brain pathological changes caused by excitatory amino acids (EAAs) toxicity and by TSE infection. Neurons mediating the neuroendocrine functions of the hypothalamus as well as Purkinje cells of the cerebellum are targets for damage by TSEs and EAAs. Both EAAs and TSE agents cause astrocytosis. TSEs commonly feature swollen astrocytes either containing abnormal prion proteins (PrPSc) or located immediately adjacent to PrPSc deposits in the neuropil. Antigenic properties of the PrPSc may stimulate the release of nearby microglial and astrocytic cytokines, resulting in dysfunction and damage to elements of the neuropil. Such swollen astrocytes also commonly occur following exposure to a number of other neurotoxicants such as EAAs. Early neuropathological changes in scrapie involve primarily astrocytes and nerve terminals, but not nerve-cell bodies or spongiform changes. These data suggest that the initial events in the pathophysiology of TSEs may be the astrocytic response to PrPSc accumulation, leading to NOS / free radical damage to nearby nerve terminals. We will review the similarities in brain pathological changes caused by TSEs and EAAs. We suggest that the end-stage neuropathology produced by TSEs has many of the characteristics of EAA-mediated neuronal necrosis, a well-established final common pathway of neurodegeneration from a variety of neurotoxicants. The cytoprotective effects of the antagonists of the NMDA receptor-channel complex such as memantine (1-amino-3,5- dimethyladamantane; MEM), MD-ADA (1-N-methylamino-3,5-dimethladamantane) or dizolcipine (MK-801, (+)-5- methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine malate) will be considered.

Prion diseases are transmissible neurodegenerative disorders of humans and animals for which no effective treatment is available. Conformationally altered, proteaseresistant forms of the prion protein (PrP), termed PrPsc, are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. Different approaches affecting the clearance of PrPsc, inhibiting or preventing its conformation change are currently under investigation. Some compounds antagonize prion propagation in cellular and / or animal models of the disease. These molecules include polyanions, polyene antibiotics, tetrapyrroles, branched polyamines and compounds termed 'beta-sheet breakers' whose direct target its the abnormal conformational change for PrPsc. The suitability of these compounds for therapy is limited, primarily because they cannot cross the blood-brain barrier (BBB) and / or show severe toxicity. A variety of drugs already used for treatment of unrelated human diseases and known to penetrate the BBB have now been screened. The tricyclic derivatives of acridine and phenothiazine inhibit PrPsc formation in scrapie-infected neuroblastoma cells, confirming earlier reports on anti-prion activity of these compounds. In addition, activation of the immune system has been proposed to increase the clearance of PrPsc and reduce the prion infectivity and antibodies can exert antiaggregation activity. We showed that tetracyclines reverse abnormal physicochemical properties and abolish the neurotoxicity of PrP peptides in vitro. These compounds interact with PrPsc from brain tissue of BSE-affected cattle and patients with new-variant Creutzfeldt-Jakob disease (vCJD). Syrian hamsters injected with tetracycline-treated inoculum showed a significant delay in the onset of clinical signs of disease and prolonged survival time. When tetracycline was pre-incubated with a high dilution of the scrapie-infected inoculum, one third of the hamsters did not develop disease. These conformation-based approaches appear to hold the most promise for prion diseases and for the neurodegenerative disorders associated with protein misfolding. Although several classes of compounds offer anti-prion action their use in clinical practice is limited by the fact they have little or no efficacy at the onset of the disease. Thus, the discovery of more efficient drugs must run in parallel with the development of diagnostic tests to identify TSE earlier.

Transmissible spongiform encephalopathies (TSEs) also called prion diseases are fatal neurodegenerative disorders of humans and animals which are unique as their origin can be infectious, genetic or sporadic. More than 80% of TSE patients have sporadic cases, 15% have familial forms and 5% iatrogenic forms. In humans, TSEs are represented by Creutzfeldt Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia and Kuru. In animals, the prominent prion diseases are scrapie of sheep and goats, bovine spongiform encephalopathy (BSE) of cattle and chronic wasting disease (CWD) of deer and elk. A critical event in TSEs is the accumulation in the central nervous system (CNS) of an abnormally folded protein, PrPSc, the protease-resistant isoform of a normal cellular protein encoded by the host and called PrPC. Until now, PrPSc isoform represented not only the best molecular marker of prion diseases but also a favorite target for therapeutic strategies.During the last decade studies on prion diseases have taken a new dimension with the BSE crisis in Europe and the emergence of a new variant of Creutzfeldt-Jakob disease (vCJD) linked to the BSE agent. Currently, no effective therapy exists for patients suffering from a clinically manifest prion disease. In addition, the multiplicity of TSE's origins and clinical forms emphasizes the difficulties of a therapeutic intervention. Indeed, it is likely that sporadic CJD which are diagnosed lately during the course of the disease request the development of a therapeutic approach that is different from that of familial prion diseases due to mutation in the PrP gene. Diagnosis, origin and stages of the disease are critical factors that should orient studies towards the development of adapted therapeutic approaches. In this article, we will review the anti-prion drugs that were identified up to now.