Neuroprotection and Enhancement of Neurite Outgrowth With Small Molecular Weight Compounds From Screens of Chemical Libraries
Introduction
Neurodevelopmental disorders and neurodegenerative diseases adversely affect a significant proportion of the world's population. For example, schizophrenia (a neurodevelopmental disorder) afflicts roughly 1% of the population (Lewis 2002, Mueser 2004), whereas Alzheimer's disease has an annual incidence rate of 7–8% in individuals over 65 (Ferri et al., 2005). Nevertheless, few truly effective treatments are available to correct or ameliorate these serious conditions. Drugs that are available typically provide only modest improvement in those patients who show any positive response. This is not surprising because the drugs mainly treat the symptoms of the disease and not its underlying cause, for example failure of neuronal migration/synapse formation, or outright loss of neurons in particular brain regions. This situation calls for a dramatic reevaluation of our current therapeutic approaches and highlights the need for novel strategies for the treatment of neurodevelopmental and neurodegenerative disorders. For the purpose of this chapter, we will refer to these conditions collectively as brain deficit disorders. This chapter will summarize recent developments that suggest new approaches for the treatment of brain deficit disorders. The goal of these novel therapeutic strategies is to move beyond superficial treatment of symptoms by addressing fundamental deficits in neuronal function and survival. We will focus most of our attention on schizophrenia because the brain defects in this disease are representative of other neurodevelopmental disorders that are less well understood. Potential therapeutic targets will be discussed, and a plan will be outlined for discovering new drugs that provide neuroenhancement, that is, that enhance neurite outgrowth (function), optimize energy metabolism, and promote neuronal survival.
Section snippets
Brain Deficit Disorders: The Challenges
Various neurological and neuropsychiatric conditions can broadly be considered brain deficit disorders, including the neurodevelopmental disorders—schizophrenia, Rett syndrome, and autism—and the neurodegenerative diseases—Alzheimer's, Parkinson's, and Huntington's. Although these disorders have very different origins, they share certain pathological features that present great clinical challenges. Brain deficit disorders are characterized by functional loss of neurons, which may be quite
Treatment Objectives
What biological activities would be desirable in a new drug aimed at treating brain deficit disorders? As mentioned earlier, these conditions are characterized by functional loss of neurons (reduced cell viability), poor synaptic connections, and impaired energy metabolism. Therefore, a new efficacious drug would ideally provide trophic support for neurons, promote neurite/dendrite outgrowth and stabilization, and optimize glucose metabolism, thus enhancing neuronal function. Previously, we
Pathology, Etiology, and Treatment of Schizophrenia
Collectively, the neurodevelopmental disorders reveal a glaring lack of treatment options for correcting or alleviating brain deficits wrought by abnormal development. We will use schizophrenia as an example of a neurodevelopmental disorder that is amenable to the application of compound screening and structure‐based design for the discovery of novel therapeutic agents.
Schizophrenia is now widely viewed as a neurodevelopmental disorder with psychiatric symptoms (Feinberg 1982, Lewis 2002,
Screening and Identification of Novel Compounds for Drug Discovery
This section will delineate a general strategy for new drug discovery aimed at neuroprotection and promotion of neurite outgrowth. We will include discussion of issues related to structure‐based drug design.
Neurodevelopmental Disorders and Neurodegenerative Diseases
As mentioned in Section I, few drugs are available for effective treatment of most brain deficit disorders. This includes devastating neurodevelopmental disorders, such as Rett syndrome, lissencephaly, and autism, and neurodegenerative diseases, such as Alzheimer's. The neurodevelopmental disorders present a particularly difficult challenge for treatment because much of the brain pathology occurs during early development in utero (Percy, 2002). Nevertheless, a therapeutic strategy aimed at
Future Directions
In order to succeed with this novel therapeutic strategy of designing neuroenhancing drugs, significant advances will be necessary on several fronts. First, we need to gain a better understanding of the molecular mechanisms involved in neuroprotection and neurite outgrowth induced by the drugs/compounds. Initial studies implicate Gi/o proteins and PI3K‐Akt signaling pathways, but the intervening steps remain a mystery. The emerging concept of metabolic flexibility needs to be fleshed out and
Acknowledgments
The authors are grateful for research support from the National Institutes of Health (grant #MH68385).
References (217)
CNS energy metabolism as related to function
Brain Res. Brain Res. Rev.
(2000)- et al.
Effect of a nerve growth factor on glucose metabolism by sympathetic and sensory nerve cells
Biochim. Biophys. Acta
(1964) Nerve growth factor for the treatment of diabetic neuropathy: What went wrong, what went right, and what does the future hold?
Int. Rev. Neurobiol.
(2002)- et al.
Function and regulation of the pentose phosphate pathway in brain
Curr. Top. Cell Regul.
(1988) - et al.
Glucose‐6‐phosphate dehydrogenase supports the functioning of the synapses in rat cerebellar cortex
Brain Res.
(2001) Glucose/mitochondria in neurological conditions
Int. Rev. Neurobiol.
(2002)- et al.
Disrupted in schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: Implications for schizophrenia and other neurological disorders
Mol. Cell. Neurosci.
(2004) - et al.
PKB binding proteins: Getting in on the Akt
Cell
(2002) - et al.
Receptor‐independent G protein activation may account for the stimulatory effects of first‐generation H1‐receptor antagonists in HL‐60 cells, basophils, and mast cells
Biochem. Pharmacol.
(1996) The AMP‐activated protein kinase cascade—a unifying system for energy control
Trends Biochem. Sci.
(2004)