Ross Clark

Neuroprotective strategies for basal ganglia degeneration: Parkinson’s and Huntington’s diseases

There are three main mechanisms of neuronal cell death which may act separately or cooperatively to cause neurodegeneration. This lethal triplet of metabolic compromise, excitotoxicity, and oxidative stress causes neuronal cell death that is both necrotic and apoptotic in nature. Aspects of each of these three mechanisms are believed to play a role in the neurodegeneration that occurs in both Parkinsons and Huntingtons diseases. Strategies to rescue or protect injured neurons usually involve promoting neuronal growth and function or interfering with neurotoxic processes. Considerable research has been done on testing a large array of neuroprotective agents using animal models which mimic these disorders. Some of these approaches have progressed to the clinical arena. Here, we review neuroprotective strategies which have been found to successfully ameliorate the neurodegeneration associated with Parkinsons and Huntingtons diseases. First, we will give an overview of the mechanisms of cell death and the background of Parkinsons and Huntingtons diseases. Then we will elaborate on a range of neuroprotective strategies, including neurotrophic factors, anti-excitotoxins, antioxidants, bioenergetic supplements, anti-apoptotics, immunosuppressants, and cell transplantation techniques. Most of these approaches hold promise as potential therapies in the treatment of these disorders.

Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system.

This review primarily discusses work that has been performed in our laboratories and that of our direct collaborators and therefore does not represent an exhaustive review of the current literature. Our aim is to further discuss the role that gene expression plays in neuronal plasticity and pathology. In the first part of this review we examine activity-dependent changes in the expression of inducible transcription factors (ITFs) and neurotrophins with long-term potentiation (LTP) and kindling. This work has identified particular ITFs (Krox-20 and Krox-24) and neurotrophin systems (particularly the brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase-B, Trk-B system) that may be involved in stabilizing long-lasting LTP (i.e. LTP3). We also show that changes in the expression of other ITFs (Fos, Jun-D and Krox-20) and the BDNF/trkB neurotrophin system may play a central role in the development of hippocampal kindling, an animal model of human temporal lobe epilepsy. In the next part of this review we examine changes in gene expression after neuronal injuries (ischemia, prolonged seizure activity and focal brain injury) and after nerve transection (axotomy). We identify apoptosis-related genes (p53, c-Jun, Bax) whose delayed expression selectively increases in degenerating neurons, further suggesting that some forms of neuronal death may involve apoptosis. Moreover, since overexpression of the tumour-suppressor gene p53 induces apoptosis in a wide variety of dividing cell types we speculate that it may perform the same function in post-mitotic neurons following brain injuries. Additionally, we show that neuronal injury is associated with rapid, transient, activity-dependent expression of neurotrophins (BDNF and activinA) in neurons, contrasting with a delayed and more persistent injury-induced expression of certain growth factors (IGF-1 and TGFbeta) in glia. In this section we also describe results linking ITFs and neurotrophic factor expression. Firstly, we show that while BDNF and trkB are induced as immediate-early genes following injury, the injury-induced expression of activinA and trkC may be regulated by ITFs. We also discuss whether loss of retrograde transport of neurotrophic factors such as nerve growth factor following nerve transection triggers the selective and prolonged expression of c-Jun in axotomized neurons and whether c-Jun is responsible for regeneration or degeneration of these axotomized neurons. In the last section we further examine the role that gene expression may play in memory formation, epileptogenesis and neuronal degeneration, lastly speculating whether the expression of various growth factors after brain injury represents an endogenous neuroprotective response of the brain to injury. Here we discuss our results which show that pharmacological enhancement of this response with exogenous application of IGF-1 or TGF-beta reduces neuronal loss after brain injury.

EFFECTS OF INSULIN-LIKE GROWTH FACTOR ADMINISTRATION AND BONE MARROW TRANSPLANTATION ON THYMOPOIESIS IN AGED MICE

There has been considerable interest in using hormone replacement therapy to rejuvenate the involuted thymus during aging. GH and insulin-like growth factor-I (IGF-I), a mediator of GH actions, have been of particular interest because of their thymopoietic effects and the fact that their serum concentrations decline during aging. However, treatment of aging rodents with either GH or IGF-I does not restore thymus cellularity to levels present in young animals, suggesting that additional defects might limit the magnitude of their effects. In particular, deficiencies have been reported to accumulate in the bone marrow T cell precursor compartment during aging. In view of this, 18-month-old mice were administered either recombinant IGF-I, bone marrow cells from young mice, or a combination of IGF-I and young bone marrow cells. Thymus cellularity in the latter group of mice was significantly higher than in animals treated with hormone or bone marrow transplantation alone, suggesting that optimal therapies for ...

N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats.

The effect of the N-terminal tripeptide of insulin-like growth factor (IGF)-1, glycine-proline-glutamate (GPE), as a neuroprotective agent for nigro-striatal dopaminergic neurons was examined in the present study using a rat model of Parkinsons disease. A unilateral nigro-striatal lesion was induced in rats by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB). GPE (3 microgram) or its vehicle was administered intracerebroventricularly (i.c.v.) 2 h after the 6-OHDA lesion. Tyrosine-hydroxylase (TH) immunohistochemistry in the substantia nigra compacta (SNc) and the striatum were examined 2 weeks after the lesion. Following 6-OHDA injection, the number of TH immunopositive neurons in the ipsilateral SNc was reduced. The density of TH immunostaining was also reduced in the ipsilateral SNc and the striatum. Treatment with a single dose of GPE (n=9) significantly prevented the loss of TH immunopositive neurons (p<0. 001) and restored the TH immunoreactivity in both the SNc and the striatum compared with the vehicle control group (n=9, p<0.001). The results suggest that GPE showed promise as a potential treatment for Parkinsons disease.

Administration of recombinant human Activin-A has powerful neurotrophic effects on select striatal phenotypes in the quinolinic acid lesion model of Huntington's disease.

Huntington disease is characterized by the selective loss of striatal neurons, particularly of medium-sized spiny glutamate decarboxylase67 staining/GABAergic projection neurons which co-contain the calcium binding protein calbindin. Lesioning of the adult rat striatum by intrastriatal injection of the N-methyl-D-aspartate receptor agonist quinolinic acid (100 nmol) results in a pattern of striatal neuropathology seven days later that resembles that seen in the Huntington brain. Using this animal model of human Huntingtons disease we investigated the effect of daily intrastriatal infusion of the nerve cell survival molecule ActivinA (single bolus dose of 0.73 microg daily for seven days) on the quinolinic acid-induced degeneration of various striatal neuronal phenotypes. By seven days, unilateral intrastriatal infusion of quinolinic acid produced a partial but significant loss (P < 0.01) in the number of striatal neurons immunoreactive for glutamate decarboxylase (to 51.0+/-5.8% of unlesioned levels), calbindin (to 58.7+/-5.1%), choline acetyltransferase (to 68.6+/-6.1%), NADPH-diaphorase (to 47.4+/-5.4%), parvalbumin (to 58.8+/-4.1%) and calretinin (to 60.6+/-8.6%) in adult rats that were administered intrastriatal phosphate-buffered saline for seven days following quinolinic acid. In contrast, in rats that received intrastriatal recombinant human ActivinA once daily for seven days following quinolinic acid, phenotypic degeneration was significantly attenuated in several populations of striatal neurons. Treatment with ActivinA had the most potent protective effect on the striatal cholinergic interneuron population almost completely preventing the lesion induced decline in choline acetyltransferase expression (to 95.1+/-5.8% of unlesioned levels, P < 0.01). ActivinA also conferred a significant protective effect on parvalbumin (to 87.5+/-7.7%, P < 0.01) and NADPH-diaphorase (to 77.5+/-7.5%, P < 0.01) interneuron populations but failed to prevent the phenotypic degeneration of calretinin neurons (to 56.6+/-5.5%). Glutamate decarboxylase67 and calbindin-staining nerve cells represent largely overlapping populations and both identify striatal GABAergic projection neurons. We found that ActivinA significantly attenuated the loss in the numbers of neurons staining for calbindin (to 79.7+/-6.6%, P < 0.05) but not glutamate decarboxylase67 (to 61.1+/-5.9%) at seven days following quinolinic acid lesioning. Taken together these results suggest that exogenous administration of ActivinA can rescue both striatal interneurons (labelled with choline acetyltransferase, parvalbumin, NADPH-diaphorase) and striatal projection neurons (labelled by calbindin) from excitotoxic lesioning with quinolinic acid. Longer-term studies will be required to determine whether these surviving calbindin-expressing projection neurons recover their ability to express the glutamate decarboxylase67/GABAergic phenotype. These results therefore suggest that treatment with ActivinA may help to prevent the degeneration of vulnerable striatal neuronal populations in Huntingtons disease.

The IGF-I amino-terminal tripeptide glycine-proline-glutamate (GPE) is neuroprotective to striatum in the quinolinic acid lesion animal model of Huntington's disease.

Huntingtons disease is an incurable genetic neurological disorder characterized by the relatively selective degeneration of the striatum. Lesioning of the striatum in rodents using the excitatory amino acid agonist, quinolinic acid (QA), effectively mimics the human neuropathology seen in Huntingtons disease. Using this animal model of Huntingtons disease, we investigated the ability of the insulin-like growth factor-I (IGF-I) amino-terminal tripeptide glycine-proline-glutamate (GPE) to protect striatal neurons from degeneration. Adult rats received a single unilateral intrastriatal injection of QA (100 nmol) and then daily injection of either vehicle or GPE (0.3 microgram/microliter/day) into the striatum for 7 days. QA at this dose resulted in a partial lesioning of the striatum after 7 days to approximately 50% of cells of unlesioned levels in vehicle-treated animals. The major striatal neuronal phenotype, GABAergic projection neurons, were identified by immunocytochemical labeling of either glutamate decarboxylase 67 (GAD(67)) or the calcium binding protein calbindin in alternate sections. Treatment with GPE for 7 days reversed the loss in projection neurons when assessed by counts of calbindin-stained cells; however, these rescued cells did not regain immunologically detectable levels of GAD(67). GPE also significantly reversed the phenotypic degeneration of cholinergic interneurons identified by immunolabeling for choline acetyltransferase (ChAT) and NADPH diaphorase interneurons identified histochemically. GPE treatment failed to rescue the calcium binding protein interneuron populations of parvalbumin and calretinin neurons. These findings reveal that exogenous administration of GPE selectively prevents excitotoxin induced phenotypic degeneration of striatal projection neurons and cholinergic and NADPH diaphorase interneurons in an animal model of Huntingtons disease.

Recombinant Human Insulin-Like Growth Factor I (IGF-I): Risks and Benefits of Normalizing Blood IGF-I Concentrations

Recombinant human (rh) insulin-like growth factor I (IGF-I) is being developed as a therapy for short stature caused by IGF deficiency (IGFD) and also for diabetes mellitus. To complement the human efficacy and safety data, a large amount of information is available regarding the pharmacology and toxicology of rhIGF-I in animals. This review summarizes the risks and benefits of normalizing blood IGF-I concentrations in IGFD, especially with regard to carcinogenicity, and compares and contrasts safety data for rhIGF-I, recombinant human growth hormone (rhGH), and insulin. A major difference between rhIGF-I and rhGH is that rhIGF-I (like insulin) has hypoglycaemic activity, whereas rhGH opposes insulin action and is diabetogenic. In most of their actions, GH and IGF-I are similar. IGF-I mediates most of the actions of GH, so the safety of rhGH and that of rhIGF-I also share many common features. In animals, the transgenic expression of hGH has been shown to act directly, by activating the prolactin receptor, to increase the incidence of mammary and prostate tumours. In comparison, the over-expression of IGF-I in animals or the administration of rhIGF-I does not have a carcinogenic effect. In formal toxicology and carcinogenicity studies, rhIGF-I has similar effects to insulin in that it can increase food intake, body size, and the growth rate of existing tumours. In animals and humans, IGFD has many long-term detrimental effects besides short stature: it increases the risk of diabetes, cardiovascular disease, and low bone mineral density. Therefore, a case can be made for replacement therapy with rhIGF-I to normalize blood IGF-I levels and reverse the detrimental effects of IGFD.

POLLEX-Online: The Polynesian Lexicon Project Online

The Polynesian lexicon project, POLLEX, was initiated in 1965 by Bruce Biggs in order to provide a large-scale comparative dictionary of Polynesian languages. Since then, POLLEX has grown to include over 55,000 reflexes of more than 4,700 reconstructed forms in 68 languages. These data have enabled many fundamental advances in Polynesian linguistics and prehistory. At almost half a century old, POLLEX is one of the longest-standing databases of linguistic information, and has moved through various incarnations, from typewriter and edge-punched cards, through microfiche to mainframe computer. In the last few years, online databases of linguistic information have become increasingly more prevalent, representing a major shift in the way linguistics is conducted. Online databases provide many advantages over the older forms of data distribution, including high availability, more robust data storage, and easy data manipulation and searching, and they also facilitate the replication of previous studies. This paper announces the latest reincarnation of the POLLEX database as an online resource, POLLEX-Online (http://pollex.org.nz), and describes the technical implementation details.

Regulation of B and T cell development by anterior pituitary hormones

Hormones produced by the anterior pituitary gland have been implicated in the regulation of primary lymphocyte development. In order to identify endocrine factors involved in that process, several strains of mice with genetic defects resulting in a selective impairment in the production of one or more anterior pituitary-derived hormones have been analysed. This study has resulted in the classification of endocrine hormones into the following four categories (i) hormones such as prolactin with no apparent effects on primary lymphopoiesis; (ii) anabolic hormones such as growth hormone and insulin-like growth factor-I whose stimulatory effects on primary lymphopoiesis are non-lineage-specific and related to their actions as systemic mediators of growth and/or differentiation; (iii) hormones such as thyroid hormones that have an obligate role in primary B lymphopoiesis; and (iv) hormones such as oestrogens that act as negative regulators of lymphopoiesis.

Ura: A Disappearing Language of Southern Vanuatu (review)

Erromango, the largest island in southern Vanuatu, suffered even more than most Paci2c islands from the demographic collapse consequent on European contact in the nineteenth century. Epidemics reduced its population from an original several thousand to fewer than 400 by the 1930s. Historical records suggest that at least four languages were spoken on Erromango in pre-European times, but the present population all speak just one of these, namely, Sye (Crowley 1998a). Of the others, only Ura is known to us from more than brief lists of words. A few elderly Erromangans still remember it as a living language, and the present volume presents what Crowley has been able to learn from them. Ura appears originally to have been the language of northern Erromango, though the surviving speakers all live at Dillons Bay on the central west coast. In the 1870s, despite considerable population decline, the missionary Gordon estimated that perhaps one quarter of the islands people (500 of 2,000) were Ura speakers. A century later, at the time of Tryons initial survey (1970–71), the situation was much as it is today: Sye was spoken by the entire population of the island (about 600 by this time), and Ura was “all but extinct ... remembered by fewer than 10 people” (Tryon 1972:65). The story of Ura might well have ended there; but fortunately, even in the 1990s, Crowley was still able to 2nd a handful of people who could speak it. Others, including both linguists from outside (Arthur Capell, John Lynch) and Erromangans anxious to record this aspect of their cultural heritage (William Mete, Jerry Taki) are duly mentioned as having worked on Ura, but the present description is essentially based on data collected and analyzed by Crowley himself since 1996. The stages in the decline of Ura can only be speculatively sketched in, but Crowley suggests that the crucial period was the 2rst two or three decades of the twentieth