Current Drug Targets-CNS & Neurological Disorders - Volume 2, Issue 5, 2003

Poly(ADP-ribose) polymerase 1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. In response to stresses that are toxic to the genome, PARP-1 activity increases substantially, an event that appears crucial for maintaining genomic integrity. Massive PARP-1 activation, however, can deplete the cell of NAD+ and ATP, ultimately leading to energy failure and cell death. The discovery that cell death may be suppressed by PARP inhibitors or by deletion of the parp-1 gene has prompted a great deal of interest in the process of poly(ADP-ribosyl)ation. Suppression of PARP-1 is capable of protecting against cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The secondary damage of initially surviving neurons in brain stroke accounts for most of the volume of the infarcted area and the subsequent loss of brain function. Microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may therefore be a promising strategy in protecting neurons from this secondary damage, as well. As PARP-1 is now recognised as playing a role also in the regulation of gene transcription, this further increases the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenges the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. PARP(s) might regulate cell fate as essential modulators of death and survival transcriptional programs with relation to NF-κB and p53, proposing that inhibitors of poly(ADP-ribosyl)ation could therefore prevent the deleterious consequences of neuroinflammation by reducing NF-κB activity.

Inflammatory processes in the brain have been implicated in both acute and chronic neurodegenerative disease. One of the most studied inflammatory mediators in this respect is the cytokine interleukin-1 (IL-1), which has diverse actions in the central nervous system and mediates a wide variety of effects, including the host defense responses to local and systemic disease and injury. Both pre-clinical and clinical data suggest a role for IL-1 as a key mediator of cell death in acute neurodegenerative conditions, such as stroke and head injury. IL-1 has also been implicated in a number of chronic diseases, including Parkinson's and Alzheimer's disease, as well as in epilepsy. Constitutive expression of IL-1 is very low in normal brain, but is up-regulated rapidly in response to local or peripheral insults. The mechanisms regulating the expression IL-1 are not well defined, but appear to involve multiple effects on neuronal, glial and endothelial cell function. Therefore, the IL-1 system represents an attractive and intensely competitive therapeutic target.

Histamine H3 receptors were first described in the eighties but finally cloned four years ago. They are G-protein coupled, mostly presynaptic, and are involved in the control of the synthesis and / or release of different neurotransmitters both in the central nervous system and the periphery. The availabiliy of specific ligands has permitted the study of potential therapeutic applications of either stimulating or blocking the function of these receptors. There is experimental evidence that drugs targeted at histamine H3 receptors could be beneficial for neurodegenerative diseases such as Alzheimer and Parkinson's disease, epilepsy, drug abuse and several affective, appetite and sleeping disorders, among others. This review presents recent advances in this field.

Over the past decade, neurotrophic factors have generated much excitement for their potential as therapy for neurological disorders. In this regard, nerve growth factor (NGF), the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of Alzheimer's disease (AD). This interest is based on the observation that cholinergic basal forebrain (CBF) neurons which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus undergo selective and severe degeneration in advanced AD and that these neurons are dependent upon NGF and its receptors for their survival. In fact, NGF transduces its effects by binding two classes of cell surface receptors, TrkA and p75NTR, both of which are produced by CBF neurons. This review focuses on NGF / receptor binding, signal transduction, regulation of specific cellular endpoints, and the potential use of NGF in AD. Alterations in NGF ligand and receptor expression at different stages of AD are summarized. Recent results suggest that cognitive deficits in early AD and mild cognitive impairment (MCI) are not associated with a cholinergic deficit. Thus, the earliest cognitive deficits in AD may involve brain changes other than simply cholinergic system dysfunction. Recent findings indicate an early defect in NGF receptor expression in CBF neurons; therefore treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in end-stage AD and attenuating the rate of degeneration of these cholinergic neurons.

The research in Huntington's disease (HD) has been growing exponentially during the last decade, since the discovery of the genetic basis that leads to neurodegeneration. HD is one of several progressive neurodegenerative disorders, in which the underlying mutation is a CAG expansion encoding a polyglutamine tract in a specific protein, which in the case of HD, is called huntingtin. The first clinical symptoms of HD are generally psychiatric abnormalities, most commonly depression and mood disturbances. Involuntary choreiform movements and dementia develop over the next 15-20 years, and death generally results from complications derived from immobility. There is currently no cure, or even an effective therapy to offset the decline in mental and motor capabilities suffered by those affected by HD, but recent studies have started to examine the usefulness of different classes of new compounds. Among these, plant-derived, synthetic or endogenous cannabinoids have been proposed to have therapeutic value for the treatment of HD, since they act on cannabinoid CB1 receptors located in the basal ganglia circuitry, that is affected by the striatal atrophy typical of HD. Recent studies have characterized the changes in these receptors, as well as their endogenous ligands, in the basal ganglia in a variety of animal models of HD. The results are indicative that the endocannabinoid system becomes hypofunctional in this disease, which could be related to the hyperkinesia typical of the earliest phases of this disease. In addition, it has been proposed that the loss of these receptors might be involved in the process of pathogenesis itself. This, together with the well-known protective properties of cannabinoid-related compounds, suggest that, in addition to a symptomatic usefulness, cannabinoids might also serve to delay or to arrest the development of this disease. The present article will review all recent data dealing with the biochemical, pharmacological and therapeutic bases that support a potential role of cannabinoids in the pathogenesis and / or therapeutic treatment of this motor disorder.