Cellular mechanisms involved in neurodegenera- tion and neuroprotection are continuing to be explored, and this paper focuses on some novel dis- coveries that give further insight into these process- es. Oligodendrocytes and activated astroglia are likely generators of the pro-inflammatory cytokines, such as the tumor necrosis factor family and interleukin family, and these glial support cells express adhesion receptors (e.g., VCAM) and release intercellular adhesion molecules (ICAM) that have a major role in neuronal apoptosis. Even brief exposure to some substances, in ontogeny and sometimes in adulthood, can have lasting effects on behaviors because of their prominent toxicity (e.g., NMDA receptor antagonists) or because they sensi- tize receptors (e.g., dopamine D 2 agonists), possibly permanently, and thereby alter behavior for the lifespan. Cell cycle genes which may be derived from microglia, are the most-recent entry into the neuroprotection schema. Neuroprotection afforded by some common substances (e.g., melatonin) and uncommon substances [e.g., nicotine, green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), trolox], ordinarily thought to be simple radical scavengers, now are thought to invoke previously unsuspected cellular mechanisms in the process of neuroprotection. Although Alzheimer's disease (AD) has features of a continuous spectrum of neu- ral and functional decline, in vivo PET imaging and and functional magnetic resonance imaging, indi- cate that AD can be staged into an early phase treatable by inhibitors of ß and γ secretase; and a late phase which may be more amenable to treat- ment by drugs that prevent or reverse tau phospho- rylation. Neural transplantation, thought to be the last hope for neurally injured patients (e.g., Parkinsonians), may be displaced by non-neural tis- sue transplants (e.g., human umbilical cord blood; Sertoli cells) which seem to provide similar neu- rotrophic support and improved behavior - without posing the major ethical dilemma of removing tis- sue from aborted fetuses. The objective of this paper is to invite added research into the newly dis- covered (or postulated) novel mechanisms; and to stimulate discovery of additional mechanisms attending neurodegeneration and neuroprotection. Keywords: Neurodegeneration; Neuroprotection; Cell cycle genes; Cytokines; Non-neural transplantation; Sertoli cells; Human umbilical cord blood; Alzheimer disease; Oligodendrocytes; Astroglia INTRODUCTION Every so often it is important to 'rise above the dust' and get into a skybox to have a better view and appre- ciation of what is actually happening on the playing field. This review is intended to be that view from the skybox to see some of the new players on the opposing teams: neurodegeneration and neuroprotection. The new players are most likely to recruit a new audience (i.e., new investigators) and turn the tide of the game through their novelty (i.e., new mechanisms) which changes the game strategy (i.e., direction of research). There is a saying that hope springs eternal. This review is intended to help that dream become a reality.Therefore, we focus on what is seen as novel, not the generally recognized aspects of these topics. Neurodegeneration is a disabling disease that affects F.P. Graham Publishing Co. Neurotoxicity Research, 2003, VOL. 5(6). pp. 375-384 Novel Mechanisms and Approaches in the Study of Neurodegeneration and Neuroprotection. A Review. RICHARD M. KOSTRZEWA a and JUAN SEGURA-AGUILAR b a Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614- 1708, USA; b Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Casilla 70000 Santiago, Chile. kostrzew@etsu.edu (In final form: 31 October 2003) *Corresponding author. Tel: +1 423 439-6321; Fax: +1 423 439-8773; E-mail: kostrzew@etsu.edu ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2003 FP Graham Publishing Co., www.fpgrahamco.com