Curr. Med. Chem. – Central Nervous System Agents, 2005, 5, 67-81 67 1568-0150/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd. Pharmacological Manipulation of Neural Progenitor Pathways In Situ: Possibilities for Neural Restoration in the Injured Adult Brain Carla B. Mellough 1 , Andrew Wood 2 and Stefan A. Przyborski 1, * 1 School of Biological and Biomedical Science, University of Durham, South Road, Durham DH1 3LE, U.K.; 2 Wyeth Re- search, Discovery Neuroscience, Monmouth Junction, Princeton, New Jersey NJ 08852, U.S.A. Abstract: Progress over the last decade has confirmed the occurrence of de novo neurogenesis within discrete regions of the adult brain. It has been demonstrated that under certain conditions neurogenesis can be stimulated above basal levels in the adult, and that resident pools of adult progenitors can be manipulated to generate new neurons in situ. Undoubtedly, these reports prelude possibilities for applications in regenerative medicine. Much attention is now being focused on the elucidation of the discrete mechanisms that are involved in the induction of the neurogenic response in the adult brain and whether these pathways can be pharmacologically manipulated to endogenously replace lost cells and alleviate neuropa- thy. There is evidence that the re-expression of many key molecular components of the various pathways controlling cel- lular proliferation, migration and differentiation during development can be re-induced within the mature brain. Recent reports show that the expression of a number of these developmentally-associated molecules occurs in close association with adult progenitor proliferation and neurogenesis, signifying an additional role for these systems in eliciting the adult neurogenic response. Here we review the literature regarding this phenomenon, with reference to the main candidate pathways involved including bone morphogenetic protein, sonic hedgehog and Wnt signalling pathways, and discuss the progress which has been made in the use of small molecules to manipulate these pathways and affect adult neurogenesis in situ. Keywords: Neurogenesis, adult progenitors, Shh, BMPs, Wnt, pharmacological manipulation, endogenous repair. 1. INTRODUCTION The regenerative capacity of the adult mammalian central nervous system (CNS) is limited and it is generally incapable of replacing functional cells lost in the course of injury or disease. Accordingly, a neurological insult almost always results in permanent functional impairment, and as a conse- quence, many people remain incapacitated for the remainder of their lives. The personal, clinical and economic implica- tions of this are far reaching, severely affecting the quality of life of millions for people worldwide. The lack of restorative therapies following neural trauma and the significant number of increasingly prevalent neurological diseases emphasises the need for the development of novel approaches which act to allow or induce some recovery of lost or altered function in affected patients. Recently, much attention has been focused on the support of compromised neural cells or the replacement of lost neural tissues by the delivery of new populations of cells, such as neural precursor cells or stem cells, into injured or degener- ate regions of the CNS [1]. Transplanting cells to replenish lost neural populations is especially relevant in the treatment of traumatic, ischemic and degenerative cell loss. In order to achieve appropriate and functional cell replacement within damaged tissues, grafted cells must stably integrate within the correct anatomical regions, survive for extended periods *Address correspondence to this author at the School of Biological and Biomedical Science, University of Durham, South Road, Durham DH1 3LE, U.K.; Tel: +44 (0)191 3341341; Fax: +44 (0)191 3341201; E-mail: stefan.przyborski@durham.ac.uk of time, receive relevant afferents, release appropriate neu- rotransmitters and reform axonal projections to topographi- cally correct brain regions. However, numerous ethical, im- munological and functional issues, remain to be resolved in this process that have considerably slowed the development of neural transplantation therapy [2]. For example, besides the clear ethical considerations associated with the use of embryonic and foetal donor material, it has been reported that a patient suffering from Parkinson’s disease will require between 8-12 foetuses for bilateral transplants to be most effective [3]. This is undoubtedly a significant quantity of donor material for success of one transplant and the source of such material is likely to be variable and inconsistent. Furthermore, the results reported in various animal neural transplantation studies have not been reflected in man. In- deed, many clinical neural transplantation trials are incon- sistent in their outcome and in some cases cause worsening symptoms and adverse effects [4]. Depending on the source of donor cells, immunological problems can also be preva- lent which may result in hyperacute rejection of the xenograft. This, coupled with a gradual decline in the num- ber of successfully-integrated cells over time, results in the loss of a substantial proportion of the initial graft [4-6]. Xenotransplanted cells have been shown to integrate within the mammalian CNS but their long-term functional capabili- ties remain questionable and their use may risk the introduc- tion of novel diseases in humans. As research progresses, many of the current obstacles to neural transplantation are likely to be overcome and grafting cells into the CNS may offer a more immediate method to