Effects of genetic deficiency of cyclooxygenase-1 or cyclooxygenase-2 on functional and histological outcomes following traumatic brain injury in mice

<p>Abstract</p> <p>Background</p> <p>Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). Although prostaglandin lipid mediators of inflammation contribute to a variety of inflammatory responses, their importance in neuroinflammation is not clear. There are conflicting reports as to the efficacy of inhibiting the enzymes required for prostaglandin formation, cyclooxygenase (COX) -1 and COX-2, for improving outcomes following TBI. The purpose of the current study was to determine the role of the COX isoforms in contributing to pathological processes resulting from TBI by utilizing mice deficient in COX-1 or COX-2.</p> <p>Results</p> <p>Following a mild controlled cortical impact injury, the amount of cortical tissue loss, the level of microglial activation, and the capacity for functional recovery was compared between COX-1-deficient mice or COX-2-deficient mice, and their matching wild-type controls. The deficiency of COX-2 resulted in a minor (6%), although statistically significant, increase in the sparing of cortical tissue following TBI. The deficiency of COX-1 resulted in no detectable effect on cortical tissue loss following TBI. As determined by ³[H]-PK11195 autoradiography, TBI produced a similar increase in microglial activation in multiple brain regions of both COX-1 wild-type and COX-1-deficient mice. In COX-2 wild-type and COX-2-deficient mice, TBI increased ³[H]-PK11195 binding in all brain regions that were analyzed. Following injury, ³[H]-PK11195 binding in the dentate gyrus and CA1 region of the hippocampus was greater in COX-2-deficient mice, as compared to COX-2 wild-type mice. Cognitive assessment was performed in the wild-type, COX-1-deficient and COX-2-deficient mice following 4 days of recovery from TBI. There was no significant cognitive effect that resulted from the deficiency of either COX-1 or COX-2, as determined by acquisition and spatial memory retention testing in a Morris water maze.</p> <p>Conclusion</p> <p>These findings suggest that the deficiency of neither COX-1 nor COX-2 is sufficient to alter cognitive outcomes following TBI in mice.</p

Hippocampal Sclerosis of Aging, a Prevalent and High-Morbidity Brain Disease

Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5-30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available

Human Cerebral Neuropathology of Type 2 Diabetes Mellitus

The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the ‘Pubmed Era’. Recent neuroimaging studies have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer\u27s disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer\u27s Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (N = 234), 139 met inclusion criteria. These patients provided the basis for comparing the prevalence of pathological and clinical indices between well-characterized cases with (N = 50) or without (N = 89) the premortem diagnosis of diabetes. In diabetics, cerebrovascular pathology was more frequent and Alzheimer-type pathology was less frequent than in non-diabetics. Finally, a series of photomicrographs demonstrates histopathological features (including clinical–radiographical correlation) observed in brains of persons that died after a history of diabetes. These preliminary, correlative, and descriptive studies may help develop new hypotheses about CNDM2. We conclude that more work should be performed on human material in the context of CNDM2

“At ‘Amen Meals’ It’s Me and God” Religion and Gender: A New Jewish Women’s Ritual

New ritual practices performed by Jewish women can serve as test cases for an examination of the phenomenon of the creation of religious rituals by women. These food-related rituals, which have been termed ‘‘amen meals’’ were developed in Israel beginning in the year 2000 and subsequently spread to Jewish women in Europe and the United States. This study employs a qualitative-ethnographic methodology grounded in participant-observation and in-depth interviews to describe these nonobligatory, extra-halakhic rituals. What makes these rituals stand out is the women’s sense that through these rituals they experience a direct con- nection to God and, thus, can change reality, i.e., bring about jobs, marriages, children, health, and salvation for friends and loved ones. The ‘‘amen’’ rituals also create an open, inclusive woman’s space imbued with strong spiritual–emotional energies that counter the women’s religious marginality. Finally, the purposes and functions of these rituals, including identity building and displays of cultural capital, are considered within a theoretical framework that views ‘‘doing gender’’ and ‘‘doing religion’’ as an integrated experience

Inhibition of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations and Ca2+ Dysregulation in Aged Rats

The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4–6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca2+ channel (VSCC) activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling

Dose- and Time-Dependent Neuroprotective Effects of Pycnogenol® following Traumatic Brain Injury

After traumatic brain injury (TBI), both primary and secondary injury cascades are initiated, leading to neuronal death and cognitive dysfunction. We have previously shown that the combinational bioflavonoid, Pycnogenol® (PYC), alters some secondary injury cascades and protects synaptic proteins when administered immediately following trauma. The purpose of the present study was to explore further the beneficial effects of PYC and to test whether it can be used in a more clinically relevant fashion. Young adult male Sprague-Dawley rats were subjected to a unilateral moderate/severe cortical contusion. Subjects received a single intravenous (i.v.) injection of PYC (1, 5, or 10 mg/kg) or vehicle, with treatment initiated at 15 min, 2 h, or 4 h post injury. All rats were killed at 96 h post TBI. Both the cortex and hippocampus ipsilateral and contralateral to the injury were evaluated for possible changes in oxidative stress (thiobarbituric acid reactive species; TBARS) and both pre- and post-synaptic proteins (synapsin-I, synaptophysin, drebrin, post synaptic density protein-95, and synapse associated protein-97). Following TBI, TBARS were significantly increased in both the injured cortex and ipsilateral hippocampus. Regardless of the dose and delay in treatment, PYC treatment significantly lowered TBARS. PYC treatment significantly protected both the cortex and hippocampus from injury-related declines in pre- and post-synaptic proteins. These results demonstrate that a single i.v. treatment of PYC is neuroprotective after TBI with a therapeutic window of at least 4 h post trauma. The natural bioflavonoid PYC may provide a possible therapeutic intervention in neurotrauma

Synaptic loss in the inferior temporal gyrus in mild cognitive impairment and Alzheimer\u27s disease

Alzheimer\u27s disease (AD) is a slowly progressing form of dementia characterized in its earliest stages as a loss of memory. Individuals with amnestic mild cognitive impairment (aMCI) may be in the earliest stages of the disease and represent an opportunity to identify pathological changes related to the progression of AD. Synaptic loss is one of the hallmarks of AD and associated with cognitive impairment. The inferior temporal gyrus plays an important role in verbal fluency, a cognitive function affected early in the onset of AD. Unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the inferior temporal gyrus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI had significantly fewer synapses (36%) compared to individuals with no cognitive impairment. Individuals with AD showed a loss of synapses very similar to the aMCI cohort. Synaptic numbers correlated highly with Mini Mental State Examination scores and a test of category verbal fluency. These results demonstrate that the inferior temporal gyrus is affected during the prodromal stage of the disease and may underlie some of the early AD-related clinical dysfunctions