Impact of neurodegenerative diseases on human adult hippocampal neurogenesis.

Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.

The interplay of neurovasculature and adult hippocampal neurogenesis.

The subgranular zone of the dentate gyrus provides a local microenvironment (niche) for neural stem cells. In the adult brain, it has been established that the vascular compartment of such niches has a significant role in regulating adult hippocampal neurogenesis. More recently, evidence showed that neurovascular coupling, the relationship between blood flow and neuronal activity, also regulates hippocampal neurogenesis. Here, we review the most recent articles on addressing the intricate relationship between neurovasculature and adult hippocampal neurogenesis and a novel pathway where functional hyperemia enhances hippocampal neurogenesis. In the end, we have further reviewed recent research showing that impaired neurovascular coupling may cause declined neurogenesis and contribute to brain damage in neurodegenerative diseases.

Exercise-induced Nitric Oxide Contributes to Spatial Memory and Hippocampal Capillaries in Rats.

Exercise has been argued to improve cognitive function in both humans and rodents. Angiogenesis significantly contributes to brain health, including cognition. The hippocampus is a crucial brain region for cognitive function. However, studies quantifying the capillary changes in the hippocampus after running exercise are lacking. Moreover, the molecular details underlying the effects of running exercise remain poorly understood. We show that endogenous nitric oxide contributes to the beneficial effects of running exercise on cognition and hippocampal capillaries. Four weeks of running exercise significantly improved spatial memory ability and increased the number of capillaries in the cornu ammonis 1 subfield and dentate gyrus of Sprague-Dawley rats. Running exercise also significantly increased nitric oxide synthase activity and nitric oxide content in the rat hippocampus. After blocking the synthesis of endogenous nitric oxide by lateral ventricular injection of NG-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor, the protective effect of running exercise on spatial memory was eliminated. The protective effect of running exercise on angiogenesis in the cornu ammonis 1 subfield and dentate gyrus of rats was also absent after nitric oxide synthase inhibition. Therefore, during running excise, endogenous nitric oxide may contribute to regulating spatial memory ability and angiogenesis in cornu ammonis 1 subfield and dentate gyrus of the hippocampus.

A Calorie-Restricted Ketogenic Diet Reduces Cerebral Cortex Vascularization in Prepubertal Rats.

The antiepileptic effect of ketogenic diets is acknowledged but its mechanism of action is poorly understood. The present work aimed to evaluate possible effects of a calorie-restricted ketogenic diet (CRKD) on brain growth and angiogenesis in normal prepubertal rats. Two groups of prepubertal rats were fed with a standard diet (group 1) or a CRKD (group 2) for ten weeks. Then, rats were sacrificed and the thickness for the following structures was evaluated by histology: (1) cerebral cortex, (2) deep cerebral white matter, and (3) substantia nigra. The capillary density was also evaluated within: (1) cerebral cortex, (2) dentate gyrus of the hippocampus, (3) periaqueductal grey matter, and (4) substantia nigra. The results showed a smaller thickness of all the areas examined and a reduced capillary density within the cerebral cortex in the CRKD-treated group compared to the control group. These findings suggest an association between reduced angiogenesis within the cerebral cortex and the antiepileptic effects of CRKD.

VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis.

Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal "juvenile" NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an "aged" systemic milieu.

APOE-Sensitive Cholinergic Sprouting Compensates for Hippocampal Dysfunctions Due to Reduced Entorhinal Input.

Brain mechanisms compensating for cerebral lesions may mitigate the progression of chronic neurodegenerative disorders such as Alzheimer's disease (AD). Mild cognitive impairment (MCI), which often precedes AD, is characterized by neuronal loss in the entorhinal cortex (EC). This loss leads to a hippocampal disconnection syndrome that drives clinical progression. The concomitant sprouting of cholinergic terminals in the hippocampus has been proposed to compensate for reduced EC glutamatergic input. However, in absence of direct experimental evidence, the compensatory nature of the cholinergic sprouting and its putative mechanisms remain elusive. Transgenic mice expressing the human APOE4 allele, the main genetic risk factor for sporadic MCI/AD, display impaired cholinergic sprouting after EC lesion. Using these mice as a tool to manipulate cholinergic sprouting in a disease-relevant way, we showed that this sprouting was necessary and sufficient for the acute compensation of EC lesion-induced spatial memory deficit before a slower glutamatergic reinnervation took place. We also found that partial EC lesion generates abnormal hyperactivity in EC/dentate networks. Dentate hyperactivity was abolished by optogenetic stimulation of cholinergic fibers. Therefore, control of dentate hyperactivity by cholinergic sprouting may be involved in functional compensation after entorhinal lesion. Our results also suggest that dentate hyperactivity in MCI patients may be directly related to EC neuronal loss. Impaired sprouting during the MCI stage may contribute to the faster cognitive decline reported in APOE4 carriers. Beyond the amyloid contribution, the potential role of both cholinergic sprouting and dentate hyperactivity in AD symptomatogenesis should be considered in designing new therapeutic approaches. SIGNIFICANCE STATEMENT: Currently, curative treatment trials for Alzheimer's disease (AD) have failed. The endogenous ability of the brain to cope with neuronal loss probably represents one of the most promising therapeutic targets, but the underlying mechanisms are still unclear. Here, we show that the mammalian brain is able to manage several deleterious consequences of the loss of entorhinal neurons on hippocampal activity and cognitive performance through a fast cholinergic sprouting followed by a slower glutamatergic reinnervation. The cholinergic sprouting is gender dependent and highly sensitive to the genetic risk factor APOE4 Our findings highlight the specific impact of early loss of entorhinal input on hippocampal hyperactivity and cognitive deficits characterizing early stages of AD, especially in APOE4 carriers.

Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability.

Sudden unexplained death in infants, including the sudden infant death syndrome, is likely due to heterogeneous causes that involve different intrinsic vulnerabilities and/or environmental factors. Neuropathologic research focuses upon the role of brain regions, particularly the brainstem, that regulate or modulate autonomic and respiratory control during sleep or transitions to waking. The hippocampus is a key component of the forebrain-limbic network that modulates autonomic/respiratory control via brainstem connections, but its role in sudden infant death has received little attention. We tested the hypothesis that a well-established marker of hippocampal pathology in temporal lobe epilepsy-focal granule cell bilamination in the dentate, a variant of granule cell dispersion-is associated with sudden unexplained death in infants. In a blinded study of hippocampal morphology in 153 infants with sudden and unexpected death autopsied in the San Diego County medical examiner's office, deaths were classified as unexplained or explained based upon autopsy and scene investigation. Focal granule cell bilamination was present in 41.2% (47/114) of the unexplained group compared to 7.7% (3/39) of the explained (control) group (p < 0.001). It was associated with a cluster of other dentate developmental abnormalities that reflect defective neuronal proliferation, migration, and/or survival. Dentate lesions in a large subset of infants with sudden unexplained death may represent a developmental vulnerability that leads to autonomic/respiratory instability or autonomic seizures, and sleep-related death when the infants are challenged with homeostatic stressors. Importantly, these lesions can be recognized in microscopic sections prepared in current forensic practice. Future research is needed to determine the relationship between hippocampal and previously reported brainstem pathology in sudden infant death.

Dissociated signals in human dentate gyrus and CA3 predict different facets of recognition memory.

A wealth of evidence has implicated the hippocampus and surrounding medial temporal lobe cortices in support of recognition memory. However, the roles of the various subfields of the hippocampus are poorly understood. In this study, we concurrently varied stimulus familiarization and repetition to engage different facets of recognition memory. Using high-resolution fMRI (1.5 mm isotropic), we observed distinct familiarity and repetition-related recognition signal profiles in the dentate gyrus (DG)/CA3 subfield in human subjects. The DG/CA3 demonstrated robust response suppression with repetition and familiarity-related facilitation. Both of these discrete responses were predictive of different aspects of behavioral performance. Consistent with previous work, we observed novelty responses in CA1 consistent with "match/mismatch detection," as well as mixed recognition signaling distributed across medial temporal lobe cortices. Additional analyses indicated that the repetition and familiarity-related signals in the DG/CA3 were strikingly dissociated along the hippocampal longitudinal axis and that activity in the posterior hippocampus was strongly correlated with the retrosplenial cortex. These data provide novel insight into the roles of hippocampal subfields in support of recognition memory and further provide evidence of a functional heterogeneity in the human DG/CA3, particularly along the longitudinal axis.

Antidepressant-induced vascular dynamics in the hippocampus of adult mouse brain.

New neurons are continuously added to hippocampal circuitry involved with spatial learning and memory throughout life. These new neurons originate from neural stem/progenitor cells (NSPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG). Recent studies indicate that vascular reconstruction is closely connected with neurogenesis, but little is known about its mechanism. We have examined vascular reconstruction in the hippocampus of adult mouse brain after the administration of the antidepressant fluoxetine, a potent inducer of hippocampal neurogenesis. The immunohistochemistry of laminin and CD31 showed that filopodia of endothelial cells sprouted from existing thick microvessels and often formed a bridge between two thick microvessels. These filopodia were frequently seen at the molecular layer and dentate hilus of the DG, the stratum lacunosum-moleculare of the CA1, and the stratum oriens of the CA3. The filopodia were exclusively localized along cellular processes of astrocytes, but such intimate association was not seen with cell bodies and processes of NSPCs. The administration of fluoxetine significantly increased vascular density by enlarging the luminal size of microvessels and eliminating the filopodia of endothelial cells in the molecular layer and dentate hilus. Treatment with fluoxetine increased the number of proliferating NSPCs in the granule cell layer and dentate hilus, and that of endothelial cells in the granule cell layer. Thus, antidepressant-induced vascular dynamics in the DG are possibly attributable to the alteration of the luminal size of microvessels rather than to proliferation of endothelial cells.

NDEL1 was decreased in the CA3 region but increased in the hippocampal blood vessel network during the spontaneous seizure period after pilocarpine-induced status epilepticus.

Nuclear distribution factor E homolog like 1 (NDEL1) plays an important role in mitosis, neuronal migration, and microtubule organization during brain development by binding to disrupted-in-schizophrenia-1 (DISC1) or lissencephaly (LIS1). Although some evidence has suggested that DISC1 expression is altered in epilepsy, few studies have reported the relationship between NDEL1 and the etiology of epilepsy. In present study, we first investigated the expression of NDEL1 and its binding protein DISC1 after pilocarpine-induced epilepsy in male C57BL/6 mice. Data revealed that the mRNA and protein expression of NDEL1 and DISC1 in the whole hippocampus increased during the spontaneous seizure period after status epilepticus (SE). Interestingly, however, the expression of NDEL1 was decreased in the cornu ammonis 3 (CA3) and dentate gyrus (DG) regions. Moreover, SE also increased the number of blood vessels that fed the CA3 and DG regions of the hippocampus and increased the incidence of abnormalities in capillary network formation where NDEL1 protein was expressed positively. Meanwhile, the expression of phosphorylated ERK (p-ERK) was also increased during the spontaneous seizure period, with a similar expression pattern as NDEL1 and DISC1. Based on these results, we hypothesize that NDEL1 might interact with DISC1 to activate ERK signaling and function as a potential protective factor during the spontaneous seizure period after pilocarpine-induced SE.

Impact of a single bout of aerobic exercise on regional brain perfusion and activation responses in healthy young adults.

PURPOSE: Despite the generally accepted view that aerobic exercise can have positive effects on brain health, few studies have measured brain responses to exercise over a short time span. The purpose of this study was to examine the impact within one hour of a single bout of exercise on brain perfusion and neuronal activation. METHODS: Healthy adults (n = 16; age range: 20-35 yrs) were scanned using Magnetic Resonance Imaging (MRI) before and after 20 minutes of exercise at 70% of their age-predicted maximal heart rate. Pseudo-continuous arterial spin labeling (pcASL) was used to measure absolute cerebral blood flow (CBF) prior to exercise (pre) and at 10 min (post-10) and 40 min (post-40) post-exercise. Blood oxygenation level dependent (BOLD) functional MRI (fMRI) was performed pre and post-exercise to characterize activation differences related to a go/no-go reaction time task. RESULTS: Compared to pre-exercise levels, grey matter CBF was 11% (±9%) lower at post-10 (P<0.0004) and not different at post-40 (P = 0.12), while global WM CBF was increased at both time points post-exercise (P<0.0006). Regionally, the hippocampus and insula showed a decrease in perfusion in ROI-analysis at post-10 (P<0.005, FDR corrected), whereas voxel-wise analysis identified elevated perfusion in the left medial postcentral gyrus at post-40 compared to pre (pcorrected = 0.05). BOLD activations were consistent between sessions, however, the left parietal operculum showed reduced BOLD activation after exercise. CONCLUSION: This study provides preliminary evidence of regionalized brain effects associated with a single bout of aerobic exercise. The observed acute cerebrovascular responses may provide some insight into the brain's ability to change in relation to chronic interventions.

Depressive mood modulates the anterior lateral CA1 and DG/CA3 during a pattern separation task in cognitively intact individuals: a functional MRI study.

Although patients with major depressive disorder typically have a reduced hippocampal volume, particularly in the cornu ammonis 1 (CA1), animal studies suggest that depressive mood is related to the dentate gyrus (DG). In this study, our objective was to clarify which hippocampal subregions are functionally associated with depressive mood in humans. We conducted a functional MRI (fMRI) study on 27 cognitively intact volunteers. Subjects performed a modified version of a delayed matching-to-sample task in an MRI scanner to investigate pattern separation-related activity during each phase of encoding, delay, and retrieval. In each trial, subjects learned a pair of sample cues. Functional MR images were acquired at a high spatial resolution, focusing on the hippocampus. Subjects also completed the Beck Depression Inventory (BDI), a questionnaire about depressive mood. Depending on the similarity between sample cues, activity in the DG/CA3 and medial CA1 in the anterior hippocampus changed only during encoding. Furthermore, the DG/CA3 region was more active during successful encoding trials compared to false trials. Activity in the DG/CA3 and lateral CA1 was negatively correlated with BDI scores. These results suggest that the DG/CA3 is the core region for pattern separation during the encoding phase and interacts with the medial CA1, depending on the similarity of the stimuli, to achieve effective encoding. Impaired activity in the DG/CA3, as well as in the lateral CA1, was found to be associated with depressive symptoms, even at a subclinical level.

Effects of altered levels of extracellular superoxide dismutase and irradiation on hippocampal neurogenesis in female mice.

PURPOSE: Altered levels of extracellular superoxide dismutase (EC-SOD) and cranial irradiation have been shown to affect hippocampal neurogenesis. However, previous studies were only conducted in male mice, and it was not clear if there was a difference between males and females. Therefore, female mice were studied and the results compared with those generated in male mice from an earlier study. METHODS AND MATERIALS: Female wild-type, EC-SOD-null (KO), and EC-SOD bigenic mice with neuronal-specific expression of EC-SOD (OE) were subjected to a single dose of 5-Gy gamma rays to the head at 8 weeks of age. Progenitor cell proliferation, differentiation, and long-term survival of newborn neurons were determined. RESULTS: Similar to results from male mice, EC-SOD deficiency and irradiation both resulted in significant reductions in mature newborn neurons in female mice. EC-SOD deficiency reduced long-term survival of newborn neurons whereas irradiation reduced progenitor cell proliferation. Overexpression of EC-SOD corrected the negative impacts from EC-SOD deficiency and irradiation and normalized the production of newborn neurons in OE mice. Expression of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 were significantly reduced by irradiation in wild-type mice, but the levels were not changed in KO and OE mice even though both cohorts started out with a lower baseline level. CONCLUSION: In terms of hippocampal neurogenesis, EC-SOD deficiency and irradiation have the same overall effects in males and females at the age the studies were conducted.

Systemic autoimmunity in TAM triple knockout mice causes inflammatory brain damage and cell death.

The Tyro3, Axl and Mertk (TAM) triply knockout (TKO) mice exhibit systemic autoimmune diseases, with characteristics of increased proinflammatory cytokine production, autoantibody deposition and autoreactive lymphocyte infiltration into a variety of tissues. Here we show that TKO mice produce high level of serum TNF-α and specific autoantibodies deposited onto brain blood vessels. The brain-blood barrier (BBB) in mutant brains exhibited increased permeability for Evans blue and fluorescent-dextran, suggesting a breakdown of the BBB in the mutant brains. Impaired BBB integrity facilitated autoreactive T cells infiltrating into all regions of the mutant brains. Brain autoimmune disorder caused accumulation of the ubiquitin-reactive aggregates in the mutant hippocampus, and early formation of autofluorescent lipofuscins in the neurons throughout the entire brains. Chronic neuroinflammation caused damage of the hippocampal mossy fibers and neuronal apoptotic death. This study shows that chronic systemic inflammation and autoimmune disorders in the TKO mice cause neuronal damage and death.

Congruence of vascular network remodeling and neuronal dispersion in the hippocampus of reelin-deficient mice.

In the hippocampus, neurons and fiber projections are strictly organized in layers and supplied with oxygen via a vascular network that also develops layer-specific characteristics in wild-type mice, as shown in the present study for the first time in a quantitative manner. By contrast, in the reeler mutant, well known for its neuronal migration defects due to the lack of the extracellular matrix protein reelin, emerging layer-specific characteristics of the vascular pattern were found to be remodeled during development of the dentate gyrus. Remarkably, in the first postnatal week, when a granule cell layer was still discernable in the reeler dentate gyrus, also the reeler vascular pattern resembled wild type. Thus, at postnatal day 6, unbranched microvessels traversed the granule cell layer and bifurcated when reaching the subgranular zone. Only after the first postnatal week vascular network remodeling in the reeler dentate gyrus became apparent, when the proportion of dispersed granule cells increased. Hence, vessel bifurcation frequency decreased in the maturing reeler dentate gyrus, but increased in wild type, resulting in significant differences (approx. 100%; p < 0.01) between adult wild type and reeler. Moreover, layer-specific vessel bifurcation frequencies disappeared in the maturing reeler dentate gyrus. Finally, a wild type-like vascular pattern was also found in the dentate gyrus of mice deficient for the reelin receptor very low density lipoprotein receptor (VLDLR), precluding a requirement of VLDLR for normal vascular pattern formation in the dentate gyrus. In sum, our findings show that vascular network remodeling in the reeler dentate gyrus is closely linked to the progression of granule cell dispersion.

Vascular changes in rat hippocampus following a high saturated fat and cholesterol diet.

The long-term effects of a diet rich in saturated fat and cholesterol on the hippocampus were evaluated in this study. It has previously been shown that this type of diet is detrimental to health, particularly affecting peripheral organs such as the heart and liver. However, effects on the brain have not been fully evaluated. This study focused on the hippocampus, a brain region instrumental for learning and memory and vulnerable to ischemic damage. Reduced blood-brain barrier (BBB) integrity and increased microgliosis were observed in the hippocampus of rats fed a high-saturated-fat and cholesterol (HFHC) diet for 6 months. Interestingly, an increase in hippocampal protein levels of occludin, a tight junction protein, was found in HFHC-treated rats as well. Further investigation revealed decreased expression of the occludin protein in blood vessels and increased expression in the dentate gyrus hilar neurons and mossy fibers of the hippocampal cornus ammonis 3 in HFHC-treated rats. Our results show alterations in BBB integrity and expression of tight junction proteins after long-term exposure to HFHC diet in rats. These findings may suggest a biologic mechanism for previously observed behavioral deficits occurring in rats fed this diet.

Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity.

Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while monitoring CA1 and CA3/dentate for separation and completion-like signals using high-resolution fMRI. In the CA1, activity varied in a graded fashion in response to increases in the change in input. In contrast, the CA3/dentate showed a stepwise transfer function that was highly sensitive to small changes in input.

Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults.

There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age-related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age-related neural changes in the human hippocampus using high-resolution (1.5 mm isotropic) blood-oxygenation level-dependent fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared with young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging.

Short-term environmental enrichment enhances adult neurogenesis, vascular network and dendritic complexity in the hippocampus of type 1 diabetic mice.

BACKGROUND: Several brain disturbances have been described in association to type 1 diabetes in humans. In animal models, hippocampal pathological changes were reported together with cognitive deficits. The exposure to a variety of environmental stimuli during a certain period of time is able to prevent brain alterations and to improve learning and memory in conditions like stress, aging and neurodegenerative processes. METHODOLOGY/PRINCIPAL FINDINGS: We explored the modulation of hippocampal alterations in streptozotocin-induced type 1 diabetic mice by environmental enrichment. In diabetic mice housed in standard conditions we found a reduction of adult neurogenesis in the dentate gyrus, decreased dendritic complexity in CA1 neurons and a smaller vascular fractional area in the dentate gyrus, compared with control animals in the same housing condition. A short exposure -10 days- to an enriched environment was able to enhance proliferation, survival and dendritic arborization of newborn neurons, to recover dendritic tree length and spine density of pyramidal CA1 neurons and to increase the vascular network of the dentate gyrus in diabetic animals. CONCLUSIONS/SIGNIFICANCE: The environmental complexity seems to constitute a strong stimulator competent to rescue the diabetic brain from neurodegenerative progression.

Therapeutic potentials of an artificial oxygen-carrier, liposome-encapsulated hemoglobin, for ischemia/reperfusion-induced cerebral dysfunction in rats.

We performed this study to elucidate whether a newly developed liposome-encapsulated hemoglobin, TRM-645 (TRM), can prevent cerebral dysfunction resulting from acute ischemic stroke when used as an oxygen carrier. Hippocampal long-term potentiation (LTP) in the perforant path-dentate gyrus synapses and anxiety-related behaviors in the elevated plus-maze test were evaluated as indices of cerebral functional outcomes in the rat with two-vessel occlusion (2VO), which was induced by 10-min clamping of bilateral common carotid arteries. Saline or TRM (hemoglobin concentration of 6 g/dl: 2.5 or 5 ml/kg) was administered via the tail vein immediately after ischemic insult. Hippocampal LTP formation was markedly impaired and the open arm durations in the elevated plus-maze decreased significantly 4 days after 2VO, compared to those of sham-operated (control) rats, suggesting the hippocampal synaptic dysfunction and anxiogenic properties in 2VO rats. TRM (5 ml/kg) restored the hippocampal LTP formation and normalized the anxiety-related behavior. TRM also improved the decreased tissue oxygen partial pressure in the 2VO rat hippocampus, possibly due to oxygen delivery to ischemic regions. Liposome-encapsulated hemoglobin TRM might have therapeutic potentials for protecting the brain from neurological complications associated with acute ischemic stroke, as a promising blood substitute for oxygen therapy.