Nitric oxide (NO) is an important regulatory molecule for the host defense that plays a fundamental role in the cardiovascular, immune, and nervous systems. NO is synthesized through the conversion of L-arginine to L-citrulline by the enzyme NO synthase (NOS), which is found in three isoforms classified as neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). Recent evidence supports the theory that this bioactive molecule has an influential role in the disruption of normal brain and vascular homeostasis, a condition known to elucidate chronic hypoperfusion which ultimately causes the development of brain lesions and the pathology that typify Alzheimer disease (AD). In addition, vascular NO activity appears to be a major contributor to this pathology before any overexpression of NOS isoforms is observed in the neuron, glia, and microglia of the brain tree, where the overexpression the NOS isoforms causes the formation of a large amount of NO. We hypothesize that since an imbalance between the NOS isoforms and endothelin-1 (ET-1), a human gene that encodes for blood vessel constriction, can cause antioxidant system insufficiency; by using pharmacological intervention with NO donors and/or NO suppressors, the brain lesions and the downstream progression of brain pathology and dementia in AD should be delayed or minimized.

The purpose of this study was to evaluate the efficacy of an integrative treatment approach on cognitive performance. The study sample comprised 35 medically ill patients (20 male, 15 female) with an average age of 71.05, who were diagnosed with mild dementia and depression. These patients were evaluated at baseline and at six, 12, and 24 months of treatment, which included antidepressants (sertraline, citalopram, or venlafaxine XR, alone or in combination with bupropion XR), cholinesterase inhibitors (donepezil, rivastigmine or galantamine), as well as vitamins and supplements (multivitamins, vitamin E, alpha-lipoic acid, omega-3 and coenzyme Q-10). Patients were encouraged to modify their diet and lifestyle and perform mild physical exercises. Results show that the integrative treatment not only protracted cognitive decline for 24 months but even improved cognition, especially memory and frontal lobe functions.

Lesons of the cholinergic nucleus basalls of Meynert elevate the ex Wivo synthesis of ( amyloid precursor protein (f-APP) In the cerebral cortex, a major projection region. We have found that this elevation is reflc by Icased levels of f-APP mRNA. The induction is rapid (occurring 60 min after placement of the lsion) and perstent (remaning for at least 45 days after esloning (-APP in that numerous other proteins, including glial fibrillary acidic protein, were not affected.We have now characterized this lesion-induced (-APP expression more completely and report that (i) the elevated ex vivo synthesis is due to increased levels of(3-APP mRNA; (ii) the (-APP response to the lesion is rapid (exhibited within 60 min of lesioning) and persistent (remaining as long as 45 days post-lesion); (iii) the induction is reversible, requiring the attenuation of neurotransmitter release but not the loss of the subcortical neurons; (iv) subcortical lesions of the cortically projecting noradrenergic and serotonergic systems similarly induce cortical (-APP expression; and, finally, (v) other general perturbations of central nervous system function fail to induce the elevated (-APP synthesis response. These results suggest a cause and effect relationship between lesioninduced neurotransmitter deficits and (-APP induction, providing a possible linkage between subcortical neurotransmitter system deficits and amyloid deposition in the AD brain. METHODSPlacement of Lesions. Adult (-8 weeks old) male SpragueDawley rats (t225-250 g) purchased from Charles River Breeding Laboratories were subcortically lesioned at the following sites: (i) unilateral lesions of the nbM with N-methyl-D-aspartate (NMDA, 50 nM) as the excitotoxin as described (3); (ii) unilateral lesions of the ascending noradrenergic bundle (ANB) with 6-hydroxydopamine (2 p1 of a 4 iLg/ml solution) as described (4); (iii) dorsal raphe nucleus (DRN) lesions with 5,7-dihydroxytryptamine (50 mM) as described (5). Controls for the nbM and ANB lesions were the contralateral cortices, whereas controls for the DRN lesions were sham-operated animals. This latter shamoperated group also served as controls for any nonspecific contralateral effects produced by the unilateral nbM and ANB lesions.TransIent Inhibition of Corticl Acetylchoine (ACh) Release. A total of 12 male Long Evans hooded rats (300-325 g) was used in this experiment. Each rat was anesthetized with chloral hydrate (400 mg/kg, i.p.) and was positioned in a Kopfstereotaxic apparatus. A 28-gauge cannula was lowered into the region of the nbM (Bregma -0.5, ±3.0, -7.7). One-half of the rats were randomly assigned to group I and also received a 2-mm microdialysis probe (CMA/12; Bioanalytical Systems, West Lafayette, IN) that was stereotaxically directed at the frontal cortex at coordinates Bregma

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