Brain functions deficits

The proposal that NO or its reactant products mediate toxicity in the brain remains controversial in part because of the use of non-selective agents such as those listed above that block NO formation in neuronal, glial, and vascular compartments. Nevertheless, a major area of research has been into the potential role of NO in neuronal excitotoxicity. Functional deficits following cerebral ischaemia are consistently reduced by blockers of NOS and in mutant mice deficient in NOS activity, infarct volumes were significantly smaller one to three days after cerebral artery occlusion, and the neurological deficits were less than those in normal mice. Changes in blood flow or vascular anatomy did not account for these differences. By contrast, infarct size in the mutant became larger... 

Drawing all this evidence together, Schildkraut (1965) concluded that depression was caused by a functional deficit of noradrenergic transmission in the brain. He also thought that the rebound depression and fatigue, which are experienced after the arousing effects of amphetamine have worn off, were due to depletion of neuronal stores of noradrenaline. However, Schildkraut made a clear distinction between the effects of antidepressants and the arousal induced by amphetamine, describing the latter as stimulation and excitement . To this day, there is controversy over whether or not amphetamine has a beneficial effect in depression. 

Acetylcholine has been implicated in learning and memory in all mammals, and the gross deficits in memory found in patients suffering from Alzheimer s disease have been ascribed to a defect in central cholinergic transmission. This transmitter has also been implicated in the altered mood states found in mania and depression, while many different classes of psychotropic drugs are known to have potent anticholinergic properties which undoubtedly have adverse consequences for brain function. 

If the functional deficit in AD is the result of neuronal and synapse loss, the ideal strategy would be to use techniques to reestablish neuronal and synaptic viability. In this sense, trophic factors are very promising. The positive results obtained in animal models of AD with brain tissue implantations with NGF and the memory enhancement and learning from laboratory animals treated with NGF have opened new windows to the possibility of the clinical use of NGF to treat AD. However, the potential benefits of the NGF may be counterbalanced by its capacity to increase the P-APP synthesis, consequently having an adverse effect in the progression of the illness. The increase of the APP synthesis may not necessarily affect all APP isoforms equally. The possibility of aberrant synapses and of alterations in the metabolism of the t- and P-amyloid protein exists [F. Hefti et al. 1995). 

Evaluation of memory and orientation is critical to the differentiation of a psychiatric versus a nonpsychiatric medical disorder. Memory for immediate, recent, and remote events can be readily tested, as well as orientation to time, place, person, space, and situation. Assuming the level of anxiety is not sufficient to impair responses to questions in these areas, deficits usually imply some impairment of brain functioning, which may or may not be reversible. 

Cellular therapy is the replacement of lost or dysfunctional tissues with new ones. Various cell types have been evaluated and considered for therapy. In the CNS, fetal neuronal tissue has been particularly evaluated for its merit in treating neurological diseases and injuries [1]. While numerous experimental and clinical transplantation studies showed that fetal neuronal transplants improve functional deficits in models of CNS diseases [2-5], others reported less positive outcomes [6, 7]. In addition, the rate of survival of fetal neuronal cells transplanted into the adult brain is relatively low, requiring large quantities of tissue, generally from several fetuses, for therapy. Researchers are looking at other opportunities for cellular therapy, particularly in the CNS. 

The aforementioned findings in rodents mirror results observed in dogs subjected to cardiac arrest with subsequent postischemic mild hypothermia of 1- to 12-h duration (38-44). For example, a 12-h period of 34°C hypothermia with hemodilution and elevated blood pressure reduced brain injury (e.g., hippocampus, neocortex, basal ganglia) and lessened functional deficits after cardiac arrest. However, in all of these studies the survival time was 4 d or less, and thus it has yet to be proven that postischemic hypothermia can permanently reduce ischemic brain injury in the dog. Based on the rodent literature, it would be useful to investigate more protracted bouts of mild hypothermia and assess longterm outcome in this intensive cardiac arrest model in the dog. 

Schwarting RKW, Huston JP (1996a) The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Prog Neurobiol 50 275-331. 

Prior to the era of in vivo brain functional imaging, this was based on human and animal lesion studies, with remarkable foresight. Spatial orientation deficits (Teuber and Proctor, 1964) are thought to reflect deficits of the posterior cortices and set-shifting impairment has been thought to reflect mostly frontal functions (Taylor et al., 1986). 

More recently, PBT2, an 8-hydroxy quinoline with increased blood-brain barrier permeability has been developed (Adlard et al., 2008) and in a 12-week phase-IIa clinical trial of AD subjects reversed frontal lobe functional deficits and significantly decreased APi 42 levels in CSF (Lannfelt et al., 2008). Together, these data suggest modulation of Zn may be an effective potential therapeutic target in AD. 

Approximately 7% of all live-born humans bear birth defects. This value may be as high as 10% if children are evaluated to age 10 years to include subtle structural or functional deficits such as minimal brain dysfunction or attention deficit disorders. More than 560 000 lives out of 3 million births per year in the United States are lost through infant death, spontaneous abortion, stillbirths, and miscarriage due presumably to defective fetal development. The relative contributions to human teratogenesis have been estimated as follows known germinal mutations, 20% chromosomal and gene aberrations, 3-5% environmental causes such as radiation, <1% infections, 2% or 3% maternal metabolic imbalance, 1% or 2% drugs and environmental chemicals, 4% or 5% contributions from maternal dietary deficiencies or excesses and... 

In various brain areas neuronal histamine release and synthesis is regulated presynaptically by histamine H3 receptors [1]. Recent studies revestl that H3 receptors not only act as autoreceptors to regulate the release euid synthesis of histamine [2, 3], but also modulate the release of other neurotransmitters, like acetylcholine [4], serotonin [5], dopamine [6] and noradrenaline [7]. In view of these widespread modulatory activities of the histamine H3 receptors, important roles for this receptor subtype in the various mammalian brain functions have been indicated [8, 9]. Consequently, selective ligands for the H3 receptor have been suggested to be benificial in the treatment of e.g. epilepsia, Alzheimer disease, sleeping and attention-deficit disorders [10, 11,12, 13, 14, 15,16],... 

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