Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.
Because functional impairment is one of the main consequences of the dementing process, patients are no longer able to engage in meaningful activities on their own. Demented patients cannot pursue hobbies because of apraxia; they cannot read because of comprehension difficulties and they cannot engage in social activities because of aphasia. Meaningful activities may improve depression, diminish agitation, apathy, insomnia and repetitive vocalization and should be attempted. Meaningful activities are important at all stages of dementing illnesses. Individuals with advanced dementia need stimulation with appropriate activities because few, if any, patients with AD progress to the persistent vegetative state (Volicer et al., 1997).
AbstractThe dopamine D3 receptor is predominantly expressed in limbic regions of the brain, such as the nucleus accumbens, island of Calleja and hippocampus, and is known to be associated with cognitive and emotional functions. This neuroanatomical distribution suggests that D3 receptors may be important targets for the development of therapeutic treatments for schizophrenia and drug abuse. Several new compounds have been reported to display a greater selectivity for D3 receptors than D2 receptors. For instance, both PD 128907 and 7-OH-DPAT were characterised as D3 preferring receptor agonists in both binding and cellular studies, with the former compound being the most selective. Recent studies have suggested that the D3 receptor subtype plays a pivotal role in the reinforcing effects of cocaine. The D3 receptor may thus be a useful target for drug development of anticocaine medications. However, therapies based on mimicking the acute effects of abused drugs may be ineffective on compulsive drug-seeking, drug craving and relapse, which are the common critical problems in the treatment of drug addiction. Hence, liability for dependence on dopamine D3 receptor agonists is a risk to be taken into consideration. The close association of the D3 receptor with mesolimbic dopaminergic circuits suggests that partial blockade of the D3 receptor may selectively decrease the rewarding effects of cocaine without contributing to the dysphoria associated with cocaine withdrawal. The selective and partial D3 receptor agonist BP 897 has the unprecedented property of reducing cocaine-seeking behaviour maintained by a cocaine-associated cue. Compounds like BP 897 could be useful for reducing relapse vulnerability, with minimal liability of dependence. A review of recent patents of the dopamine agonists in the last four years suggest some potential therapeutic benefits from this class of drugs to treat psychiatric and neurologic diseases. It also outlines the utility of dopamine agonists in various new indications.Keywordscocaine addictiondopamine agonistpramipexole
Aging of the brain is accompanied by multiple changes in morphology and functional variations at the cellular and molecular levels of nerve cells. Neuritic plaques, one of the two diagnostic brain lesions observed in Alzheimer's original patient, are microscopic foci of extracellular amyloid deposition. They are associated with axonal and dendritic injury, and are generally found in large numbers in the limbic and association cortices (Dickson, 1997).
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