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Rats were subjected to bilateral carotid artery occlusion (2-VO) or sham occlusion (No-VO) and tested 12 weeks for visuo-spatial memory (VSM) function. After 14 weeks, 2-VO rats (N = 4) showing severe visuo-spatial memory impairment were given dimethyl sulfoxide (DMSO)-fructose 1,6-diphosphate (FDP) i.p. for seven days and retested on the water maze. After DMSO-FDP, a 54% improvement in their VSM was seen which nearly reached control No-VO values. Untreated 2-VO (N = 4) and No-VO (N = 8) rats showed no significant changes in their VSM. DMSO-FDP treatment was discontinued and rats were retested on the water maze but improvement was lost and VSM function regressed to pretreatment levels. Immunohistochemical examination showed minimal neuronal damage in all 2-VO rats and slight loss of microtubule associated protein-2. Glial fibrillary acidic protein immunostaining increase was observed only in untreated 2-VO rats. The results indicate that a DMSO-FDP combination improves VSM secondary to chronic brain hypoperfusion.

Ten-month-old rats were subjected to permanent bilateral occlusion of both common carotid arteries (2-VO) to chronically but moderately reduce brain blood flow. 2-VO impaired Morris water maze acquisition as soon as 7 days post-surgery. 2-VO also caused a later-appearing impairment on the radial arm maze which did not reach significance until 63 days post-surgery. At 14 dats post-surgery there were no effects of 2-VO on hippocampal CA1 pyramidal cell number or density of glial fibrillary acidic protein (GFAP). Hippocampal choline acetyltransferase activity at 70 days was also unaffected by 2-VO. At 190 days post-surgery, however, the 2-VO rats showed loss of cells and increased GFAP density in CA1. The increased density of hippocampal GFAP correlated with radial arm maze but not Morris water maze impairment. It is suggested that 2-VO causes neuronal dysfunction which can be exacerbated by stress and thereby manifested on aversively motivated tasks such as the water maze. As well, CA1 neurons begin to degenerate after several weeks of the reduced energy availability caused by 2-VO and this impairs memory. Since reduced neuronal energy metabolism is associated with the progressive neurodegeneration that underlies disorders such as Alzheimer's, research should further explore the possibility that the effects of 2-VO may model age-related dementia.

Middle aged rats (13 months) were subjected to chronic cerebrovascular insufficiency (CVI) for 9 weeks using a 3-vessel occlusion technique. This CVI injury targets CA1 neuron damage selectively. Three groups of rats had their cerebral blood flow restored after 1, 2 or 3 weeks following CVI by removal of their carotid artery occluders. Another rat group did not undergo deocclusion for the 9 week observation period. Rats were tested for memory acquisition and retention 6 and 9 weeks after CVI using a modified water maze test. At the end of the 9 weeks, cerebral blood flow was measured in the fronto-parietal cortex and rats were killed by fixation-perfusion. Hippocampal morphometry was done to assess the % of damaged CA1 neurons and the density of GFAP-positive hyperplasia and hypertrophy. Results show that restoration of cerebral blood flow 1 and 2 weeks after CVI but not after 3 weeks of CVI, reversed a significant increase in reactive astrocytosis and prevented memory impairment in these deoccluded rats when compared to the non-deoccluded group. It appears from these results that 'neuronal rescue' of CA1 neurons is possible when cerebral blood flow is restored in rats subjected to chronic CVI during a 2 week (but not 3 week) 'window of opportunity'. This chronic brain ischemia model may be useful in screening potential therapy in patients with dementia where spatial memory impairment and hippocampal damage may be manifested.

Following complete transection of the spinal cord, cats were separated into 2 groups to undergo: (i) surgical reconstruction of the disconnected cord using a neuroactive agent mixed into a collagen matrix bridge and omental transposition and (ii) cord transection-only. After 90 days, animals were killed and the brain and spinal cord were removed for immunohistochemistry. Two weeks prior to sacrifice, spinal cord blood flows were measured and the retrograde axonal tracer Fluoro-Gold was injected below the transection site. Gross inspection of the spinal cords at autopsy showed excellent integration and continuity of the collagen matrix bridge with the proximal-distal stumps in the surgical reconstruction group. In the transection-only group, the proximal-distal stumps were connected by a fibrotic, often tapered in the middle, tissue bridge. Results show that omental transposition in the surgical reconstruction group increased spinal cord blood flow by 58% when compared to transection-only animals. Fluoro-Gold was found in mesencephalic and brainstem catecholaminergic and cholinergic neurons known to send axons to the spinal cord. Immunohistochemical staining with antibodies against catecholamine synthesizing enzymes tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) showed that surgical reconstruction treated cat cords but not transection-only, developed dense bundles of dopaminergic and noradrenergic fibers which were present in the collagen matrix bridge and in the distal spinal cord. Extension of these catecholaminergic fibers in surgical reconstruction treated cats showed maximal outgrowth of 90 mm below the transection site when the neuroactive agent 4-aminopyridine was mixed into the collagen matrix. In addition, the synaptogenic marker synaptophysin (SYN) was observed on preganglionic sympathetic neurons in association with dopaminergic- and noradrenergic-containing varicosities distal to the collagen matrix bridge, an indication that neo-synaptic contacts may have been made on these previously denervated neurons. No TH, DBH or SYN was observed below the transection site in transection-only cats. These findings indicate that surgical reconstruction treated cords can develop dense supraspinal fiber outgrowth across a treated collagen matrix bridge fed by an omental blood supply and that these fibers may have made neo-synaptic contacts with appropriate distal spinal cord target tissue.

Young and aged rats were subjected to cerebrovascular insufficiency (CVI) for 3 and 9 weeks. At the end of each time period, local cerebral blood flow (lCBF), spatial memory function, 31P- and 1H-NMR spectroscopy and imaging of the brains were evaluated in vivo. Morphometric counts of CA1 hippocampal neuron damage and staining for glial fibrillary acidic protein (GFAP) were done post-mortem. Results show that after 3 weeks of CVI, cortical and hippocampal lCBF was significantly reduced in young and aged animals respectively. In addition, young and aged rats at 3 weeks following CVI showed spatial memory deficits in the Morris water maze and elevation of 31P-phosphomonoester as measured by non-invasive NMR spectroscopy. At the same time period, in vivo 1H-microimaging (MRI) of brains showed areas of high signal intensity (suggesting local edema) localized asymmetrically to the right hippocampal region in young and aged CVI rats. Morphometry of the hippocampal CA1 sector at post-mortem confirmed the in vivo MRI changes and demonstrated that a significant percentage of the CA1 pyramidal cells were damaged after CVI. Nine weeks after CVI, hippocampal CBF reductions, spatial memory impairment, spectroscopic-microimaging changes and CA1 sector cell damage continued to be observed in the aged animals but were resolved in the young rat brains. In addition, GFAP immunoreaction progressively increased in the hippocampus of aged rats subjected to CVI for 9 weeks. It is concluded that cognitive, metabolic and morphologic damage was significantly more severe and longer lasting in aged than young rat brain after chronic CVI. The deficits observed in this rat model appear to mimic the early pathology reported in Alzheimer's disease and suggest that the present model could provide fundamental clues relative to the etiology and possible management of this dementia.

Rat sciatic nerves were bilaterally transected and repaired with an entubulation technique. The nerve interstump gap was filled with either collagen gel or collagen gel mixed with a putative neurotrophic factor (leupeptin, 4-aminopyridine, lipid angiogenic factor or glia maturation factor beta (GMF-beta]. Six weeks after nerve transection, the myelinated distal stump axons were quantified for each nerve. Only the nerves treated with GMF-beta had significantly more axons than the control side.

Acute, progressive global brain ischemia was induced in awake or anesthetized rats for 5-75 min. Ischemia was achieved with a subclavian-carotid artery occlusion technique (SCOT). After thoracotomy, both subclavian arteries (proximal to their vertebral branches) were tied-off and carotid artery catheter-snares installed. Results show progressive morphological, physiological and neurochemical damage when CBF was reduced from preischemic levels of 115 ml to 0 blood flow. 31P magnetic resonance spectroscopy of high energy phosphate metabolites in vivo showed loss of PCr and beta-ATP signals after 6 min brain ischemia. Energy metabolite levels, EEG and CBF normalized within hours after reperfusion. Degree of neuropathologic damage to hippocampal region appeared linearly related to the ischemic duration of ischemia. Thus, acute global brain ischemia resulted in loss of high energy phosphate metabolites, EEG and neuronal integrity in the hippocampal subfields. Reperfusion following short (5 min) or long (75 min) periods of global brain ischemia induced return of 31P-spectra, EEG and CBF to normal but was unable to reverse all of the neuronal damage at the end of the 72-h observation period.

A 10% calcium chloride solution or normal physiological saline was instilled onto the intact dorsal surface of the spinal cord via a specially constructed catheter-canopy system fixed above the T9 level in conscious rats. Within 5 min after calcium instillation rats developed flaccid paralysis of the lower limbs with sensory loss. Sensory loss was accompanied by abnormal or negative evoked potentials. Rats instilled with physiological or 10% sodium chloride remained normal. Rats were sacrificed at 1, 16 and 48 h post-calcium exposure and following full functional recovery from paralysis. Spinal cords were removed for histologic and high-performance liquid chromatography (HPLC) analysis. Histologic examination for catecholamines using SPG histofluorescence showed loss of catecholamine-containing varicosities in gray matter below calcium exposure which returned to normal levels upon sensorimotor recovery of hindlimbs about 14 days pce. Light microscopic examination of vascular permeability and general morphology of cord tissue axons and neurons remained normal in calcium and saline instilled rats. HPLC analysis of spinal cord below calcium exposure, also showed norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) tissue level reductions which returned to normal upon sensorimotor recovery of paralysis about 2 weeks later. No significant changes were noted in dopamine or serotonin levels in any group. Our findings suggest an impairment of ascending and descending tract transmitter transport, specifically reflected in the noradrenergic bulbospinal pathway. The results implicate a neurofilament-microtubule disassembly in axonal cytoskeleton triggered by the sudden calcium influx.