Dwaine F. Emerich

Locomotion of aged rats: Relationship to neurochemical but not morphological changes in nigrostriatal dopaminergic neurons

Spontaneous locomotion and motor coordination was evaluated in young (5-6 month old) and aged (24-25 month old) rats. Animals were tested for spontaneous locomotor activity in Digiscan Animal Activity Monitors during the nocturnal cycle. Aged animals exhibited a significant hypoactivity compared to their young counterparts. Evaluation of the time course of activity revealed that the young animals had a cyclical pattern of activity during the 12-hour testing period with clear peaks at 2-4 hours after the initiation of testing and at 8- to 10-hour intervals thereafter. In contrast, the aged animals exhibited a blunted initial activity peak. During the remainder of the test period the aged animals activity was stable with no further peaks in activity. Compared to the young animals the aged animals also (a) remained suspended from a horizontal wire for less time, (b) were unable to descend a wooden pole covered with wire mesh in a coordinated manner, (c) fell more rapidly from a rotating rod and (d) were unable to maintain their balance on a series of wooden beams with either a square or rounded top of varying widths. Histological analysis demonstrated that there was no reduction in the number, area, or length of tyrosine hydroxylase-immunoreactive neurons within the A8, A9, or A10 region of the aged animals. Neurochemical analysis revealed that while DA and HVA levels were not decreased in the aged rats, DOPAC levels, as well as the ratios of DA/DOPAC and DA/HVA, were decreased. These results indicate that neurochemical but not morphological changes within the nigrostriatal dopaminergic system underlie the deficits in motor behavior observed in aged rats.

Transplantation of human umbilical cord blood cells in the repair of CNS diseases

Cell transplantation therapies have been used to treat certain neurodegenerative diseases such as Parkinson’s and Huntington’s disease. However, ethical concerns over the use of fetal tissues, and the inherent complexities of standardising the procurement, processing and transplantation methods of this tissue, have prompted the search for a source of cells that have less ethical stigmatisations, are readily available and can be easily standardised. Several sources of human cells that meet these principles have been under investigation. Cells from human umbilical cord blood (HUCB) are one source that is consistent with these principles; therefore, they have become of great interest in the field of cellular repair/replacement for the treatment of CNS diseases and injury. This review will focus on the advantages of HUCB cells as a source for cellular transplantation therapies, recent studies that have examined the potential of these cells in vitro to be directed towards neural phenotypes, and in vivo studies that have investigated the functional recovery of animals in a number of models of CNS injury and disease following administration of HUCB cells.

Epidemiological survey-based formulae to approximate incidence and prevalence of neurological disorders in the United States: a meta-analysis.

Background This study aims to create a convenient reference for both clinicians and researchers so that vis-à-vis comparisons between brain disorders can be made quickly and accurately. We report here the incidence and prevalence of the major adult-onset brain disorders in the United States using a meta-analysis approach. Material and Methods Epidemiological figures were collected from the most recent, reliable data available in the research literature. Population statistics were based on the most recent census from the US Census Bureau. Extrapolations were made only when necessary. The most current epidemiological studies for each disorder were chosen. All effort was made to use studies based on national cohorts. Studies reviewed were conducted between 1950 and 2009. The data of the leading studies for several neurological studies was compiled in order to obtain the most accurate extrapolations. Results were compared to commonly accepted values in order to evaluate validity. Results It was found that 6.75% of the American adult population is afflicted with brain disorders. This number was eclipsed by the 8.02% of Floridians with brain disorders, which is due to the large aged population residing in the state. Conclusions There was a noticeable lack of epidemiological data concerning adult-onset brain disorders. Since approximately 1 out of every 7 households is affected by brain disorders, increased research into this arena is warranted.

Sex differences in regulatory changes following quinolinic acid-induced striatal lesions

The effects of sex differences and hormonal factors on the weight loss following intrastriatal injections of quinolinic acid (QA) were examined. Male, female or ovariectomized female rats were weighed each day for 30 days following bilateral injections of 150 nmol of QA or vehicle into the striatum. Although all rats injected with QA exhibited an equivalent initial loss of body weight, female lesioned rats rapidly regained weight and did not differ from controls after the first postsurgical day. On the other hand, male lesioned and female ovariectomized lesioned rats exhibited a significant but transient loss of body weight. By 19 days postsurgery all rats had recovered and exhibited comparable body weights. Histological analysis did not reveal any sex-related differences in the extent of striatal pathology following QA. These results suggest that sex and hormonal variables such as estrogen levels play an important role in the regulatory changes following excitotoxic-induced striatal damage.

Treatment of Central Nervous System Diseases with Polymer-Encapsulated Xenogeneic Cells

One of the major goals of neuroscience research is to develop effective treatments for clinical disorders. It is generally accepted that the discovery and development of effective, novel treatments is more efficient (i.e., faster and less costly) if those efforts are guided by a rational plan of action, based on careful consideration of the available data. Although tremendous technical and conceptual advances have been made in the neurosciences and considerable information about many neurological disorders has become available, it is still difficult to formulate a plan of action that can assure success because so many fundamental questions remain unanswered. For example, among the most problematic of the neurological disorders are those associated with the loss of brain neurons. Although we continue to learn more and more about the pathology and molecular biology of neurodegenerative diseases, congenital disorders, and strokes, very little is known about the specific mechanisms that mediate cell death. In fact, some research findings in these areas serve more to elucidate how little we truly understand about the etiology of these disorders and to stimulate the articulation of new questions that need to be addressed than to point the way toward a specific solution. As long as questions remain about the primary etiology and pathological mechanisms that mediate cell death, some uncertainty will remain about which avenues of research will produce effective preventative or palliative treatments for these disorders.

Choroid Plexus and Immune Response of the Brain

Publisher Summary The choroid plexuses (CPs), located within the ventricles of the brain, produce the cerebrospinal fluid and form an interface between the peripheral blood and the CSF. Key functions related to brain homeostasis that have been ascribed to CP include processes that establish, survey, and maintain the biochemical and cellular status of the brain under normal and pathological conditions. Therapeutic strategies exploiting the growth factor secretion and immune regulatory properties of CP may prove directly relevant to treating brain disorders. Indeed, the transplant studies conducted to date lend support to the use of CP for repairing the diseased and/or aging brain. Subsequent studies are needed to clearly elucidate the mechanisms of action by which these therapeutic benefits are achieved with CP, in order to further improve the functional outcomes. Envisioned mechanism-driven experiments include determining whether CP functions within parenchymal tissue in the same manner as within the CSF, and conducting vis-a-vis comparisons between native ability of CP to secrete a physiologically balanced and temporally adjusted cocktail of bioactive compounds versus delivery of single agents. Critical to advancing CP cell therapy are translational research issues such as examining the potential clinical indication with emphasis on optimizing the donor source and age of the transplanted cells, determining whether specific cell types within the are most beneficial, and identifying the optimal postinjury timing, transplant location and dosage, of cells to be grafted into the CNS.

Neural basis of behavior : animal models of human conditions

A variety of neurological disorders including Alzheimers, Parkinsons, and Huntingtons diseases are characterized by abnormalities within specific neuroanatomical and/or neurochemical systems. Approaches to the treatment of these and other neurological disorders are limited. The development and refinement of animal models which closely mimic human disease states would help elucidate the underlying neurobiological mechanisms of the disease as well as suggest novel therapeutic strategies for their prevention or alleviation. This symposium presents a variety of animal models that have helped us in understanding the human condition. The present introduction presents some clinically relevant findings obtained from basic experimental studies with animal models of Huntingtons disease (HD) and Tourette Syndrome (TS). These studies demonstrate that animal models can provide a greater understanding of the symptomatology of disease states as well as suggest innovative new treatments.

Primary Choroid Plexus Tissue for Use in Cellular Therapy

The choroid plexus (CP) has been explored as a cellular therapeutic due to its broad-ranging secretome and demonstrated longevity in a variety of encapsulation modalities. While the CP organ is normally involved in disease repair processes in the brain, the range of indications that could potentially be ameliorated with exogenous CP therapy is widespread, including diseases of the central nervous system, hearing loss, chronic wounds, and others. The CP can be isolated from animal sources and digested into a highly purified epithelial culture that can withstand encapsulation and transplantation. Its epithelium can adapt to different microenvironments, and depending on culture conditions, can be manipulated into various three-dimensional configurations with distinct gene expression profiles. The cocktail of proteins secreted by the CP can be harvested in culture, and purified forms of these extracts have been evaluated in topical applications to treat poorly healing wounds. When encapsulated, the epithelial clusters can be maintained for extended durations in vitro with minimal impact on potency. A treatment for Parkinsons disease utilizing encapsulated porcine CP has been developed and is currently being evaluated in a Phase I clinical trial. The current chapter serves to summarize recent experience with CP factor delivery, and provides a description of the relevant materials and methods employed in these studies.

The Choroid Plexus

The choroid plexus (CP) produces cerebrospinal fluid (CSF) and forms a portion of the physical structure of the CSF-blood barrier. More recently, the CP been implicated in other basic aspects of neural functioning, such as surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive cocktail of polypeptides for neuronal function and survival, and participating in repair processes following trauma. The CP also has a role in maintaining the extracellular milieu of the brain by actively modulating the chemical exchange between the CSF and brain parenchyma and by secreting numerous growth factors into the CSF. Preclinical and clinical studies in aging and neurodegeneration demonstrate anatomical and physiological changes in the CP, suggesting effects not only in normal development and pathological conditions, but also in potential endogenous repair processes following trauma. CP dysfunction in central nervous system (CNS) diseases, and the endogenous secretion of growth factors, indicates that transplantable CP might enable delivery of growth factors to the brain while avoiding the conventional molecular and genetic alterations associated with modifying cells to secrete selected products. Thus, this enables the possibility of replacing or transplanting CP as a means of treating acute and chronic brain diseases. This chapter focuses on the various functions of the CP, how these functions are altered in aging and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.

Progress and Challenges in Immunoisolation for CNS Cell Therapy

The blood-brain barrier (BBB) hinders the delivery of potentially therapeutic drugs to the brain by restricting the diffusion of drugs from the vasculature to the brain parenchyma. One method to overcome the BBB is with cellular implants that produce and deliver therapeutic molecules directly to the brain region of interest. Immunoisolation is based on the observation that xenogeneic cells can be protected from host rejection by encapsulating, or surrounding, them within an immunoisolatory, semipermeable membrane. Cells can be enclosed within a selective, semipermeable membrane barrier that admits oxygen and required nutrients and releases bioactive cell secretions but restricts passage of larger cytotoxic agents from the host immune defense system. The selective membrane eliminates the need for chronic immunosuppression of the host and allows the implanted cells to be obtained from nonhuman sources. This chapter discusses cell immunoisolation for treating central nervous system (CNS) diseases, from concept to preclinical evaluation, in a wide range of animal models and relating to the clinical trials conducted to date.