Hippocampus under Pressure: Molecular Mechanisms of Development of Cognitive Impairments in SHR Rats.

Data from clinical trials and animal experiments demonstrate relationship between chronic hypertension and development of cognitive impairments. Here, we review structural and biochemical alterations in the hippocampus of SHR rats with genetic hypertension, which are used as a model of essential hypertension and vascular dementia. In addition to hypertension, dysfunction of the hypothalamic-pituitary-adrenal system observed in SHR rats already at an early age may be a key factor of changes in the hippocampus at the structural and molecular levels. Global changes at the body level, such as hypertension and neurohumoral dysfunction, are associated with the development of vascular pathology and impairment of the blood-brain barrier. Changes in multiple biochemical glucocorticoid-dependent processes in the hippocampus, including dysfunction of steroid hormones receptors, impairments of neurotransmitter systems, BDNF deficiency, oxidative stress, and neuroinflammation are accompanied by the structural alterations, such as cellular signs of neuroinflammation micro- and astrogliosis, impairments of neurogenesis in the subgranular neurogenic zone, and neurodegenerative processes at the level of synapses, axons, and dendrites up to the death of neurons. The consequence of this is dysfunction of hippocampus, a key structure of the limbic system necessary for cognitive functions. Taking into account the available results at various levels starting from the body and brain structure (hippocampus) levels to molecular one, we can confirm translational validity of SHR rats for modeling mechanisms of vascular dementia.

Glucocorticoids Orchestrate Adult Hippocampal Plasticity: Growth Points and Translational Aspects.

The review analyzes modern concepts about the control of various mechanisms of the hippocampal neuroplasticity in adult mammals and humans by glucocorticoids. Glucocorticoid hormones ensure the coordinated functioning of key components and mechanisms of hippocampal plasticity: neurogenesis, glutamatergic neurotransmission, microglia and astrocytes, systems of neurotrophic factors, neuroinflammation, proteases, metabolic hormones, neurosteroids. Regulatory mechanisms are diverse; along with the direct action of glucocorticoids through their receptors, there are conciliated glucocorticoid-dependent effects, as well as numerous interactions between various systems and components. Despite the fact that many connections in this complex regulatory scheme have not yet been established, the study of the factors and mechanisms considered in the work forms growth points in the field of glucocorticoid-regulated processes in the brain and primarily in the hippocampus. These studies are fundamentally important for the translation into the clinic and the potential treatment/prevention of common diseases of the emotional and cognitive spheres and respective comorbid conditions.

Role of BDNF in Neuroplasticity Associated with Alcohol Dependence.

Chronic alcohol consumption is characterized by disturbances of neuroplasticity. Brain-derived neurotrophic factor (BDNF) is believed to be critically involved in this process. Here we aimed to review actual experimental and clinical data related to BDNF participation in neuroplasticity in the context of alcohol dependence. As has been shown in experiments with rodents, alcohol consumption is accompanied by the brain region-specific changes of BDNF expression and by structural and behavioral impairments. BDNF reverses aberrant neuroplasticity observed during alcohol intoxication. According to the clinical data parameters associated with BDNF demonstrate close correlation with neuroplastic changes accompanying alcohol dependence. In particular, the rs6265 polymorphism within the BDNF gene is associated with macrostructural changes in the brain, while peripheral BDNF concentration may be associated with anxiety, depression, and cognitive impairment. Thus, BDNF is involved in the mechanisms of alcohol-induced changes of neuroplasticity, and polymorphisms within the BDNF gene and peripheral BDNF concentration may serve as biomarkers, diagnostic or prognostic factors in treatment of alcohol abuse.

Comparative Investigation of Expression of Glutamatergic and GABAergic Genes in the Rat Hippocampus after Focal Brain Ischemia and Central LPS Administration.

Among the responses in the early stages of stroke, activation of neurodegenerative and proinflammatory processes in the hippocampus is of key importance for the development of negative post-ischemic functional consequences. However, it remains unclear, what genes are involved in these processes. The aim of this work was a comparative study of the expression of genes encoding glutamate and GABA transporters and receptors, as well as inflammation markers in the hippocampus one day after two types of middle cerebral artery occlusion (according to Koizumi et al. method, MCAO-MK, and Longa et al. method, MCAO-ML), and direct pro-inflammatory activation by central administration of bacterial lipopolysaccharide (LPS). Differences and similarities in the effects of these challenges on gene expression were observed. Expression of a larger number of genes associated with activation of apoptosis and neuroinflammation, glutamate reception, and markers of the GABAergic system changed after the MCAO-ML and LPS administration than after the MCAO-MK. Compared with the MCAO-ML, the MCAO-MK and LPS challenges caused changes in the expression of more genes involved in glutamate transport. The most pronounced difference between the responses to different challenges was the changes in expression of calmodulin and calmodulin-dependent kinases genes observed after MCAO, especially MCAO-ML, but not after LPS. The revealed specific features of the hippocampal gene responses to the two types of ischemia and a pro-inflammatory stimulus could contribute to further understanding of the molecular mechanisms underlying diversity of the post-stroke consequences both in the model studies and in the clinic.

Ambiguous Contribution of Glucocorticosteroids to Acute Neuroinflammation in the Hippocampus of Rat.

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide (LPS) to the DH. The modulation of GR and MR was performed by dexamethasone (GR activation), mifepristone, and spironolactone (GR and MR inhibition, respectively). Experimental drugs were delivered to the dentate gyrus of the DH bilaterally by stereotaxic injections. Dexamethasone, mifepristone, and spironolactone were administered either alone (basal conditions) or in combination with LPS (neuroinflammatory conditions). Changes in expression levels of neuroinflammation-related genes and morphology of microglia 3 days after intrahippocampal administration of above substances were assessed. Dexamethasone alone induced a weak proinflammatory response in the hippocampal tissue, while neither mifepristone nor spironolactone showed significant effects. During LPS-induced neuroinflammation, GR activation suppressed expression of selected inflammatory genes, though it did not prevent appearance of activated forms of microglia. In contrast to GR activation, GR or MR inhibition had virtually no influence on LPS-induced inflammatory response. The results suggest glucocorticosteroids ambiguously modulate specific aspects of neuroinflammatory response in the hippocampus of rats at molecular and cellular levels.

Reduced Levels of Lacrimal Glial Cell Line-Derived Neurotrophic Factor (GDNF) in Patients with Focal Epilepsy and Focal Epilepsy with Comorbid Depression: A Biomarker Candidate.

Our previous studies showed that in patients with brain diseases, neurotrophic factors in lacrimal fluid (LF) may change more prominently than in blood serum (BS). Since glial cell line-derived neurotrophic factor (GDNF) is involved in the control of neuronal networks in an epileptic brain, we aimed to assess the GDNF levels in LF and BS as well as the BDNF and the hypothalamic-pituitary-adrenocortical and inflammation indices in BS of patients with focal epilepsy (FE) and epilepsy and comorbid depression (FE + MDD) and to compare them with those of patients with major depressive disorder (MDD) and healthy controls (HC). GDNF levels in BS were similar in patients and HC and higher in FE taking valproates. GDNF levels in LF were significantly lower in all patient groups compared to controls, and independent of drugs used. GDNF concentrations in LF and BS positively correlated in HC, but not in patient groups. BDNF level was lower in BS of patients compared with HC and higher in FE + MDD taking valproates. A reduction in the GDNF level in LF might be an important biomarker of FE. Logistic regression models demonstrated that the probability of FE can be evaluated using GDNF in LF and BDNF in BS; that of MDD using GDNF in LF and cortisol and TNF-α in BS; and that of epilepsy with MDD using GDNF in LF and TNF-α and BDNF in BS.

Development of Post-Stroke Cognitive and Depressive Disturbances: Associations with Neurohumoral Indices.

Neuropsychiatric complications, in particular cognitive and depressive disorders, are common consequences of ischemic stroke (IS) and complicate the rehabilitation, quality of life, and social adaptation of patients. The hypothalamic-pituitary-adrenal (HPA) system, sympathoadrenal medullary system (SAMS), and inflammatory processes are believed to be involved in the pathogenesis of these disorders. This study aimed to explore these systems in IS patients, including those with post-stroke cognitive and depressive disorders, within a year after IS. Indices of the HPA axis, inflammatory system, and SAMS were measured in blood serum (cortisol, interleukin-6 (IL-6)), plasma (adrenocorticotropic hormone), and saliva (cortisol, α-amylase). During one year after mild/moderate IS (NIHSS score 5.9 ± 4.3), serum cortisol and salivary α-amylase levels remained elevated in the total cohort. In the group with further cognitive decline, serum and salivary cortisol levels were elevated during the acute period of IS. In the group with poststroke depressive disorder, salivary α-amylase was constantly elevated, while serum IL-6 was minimal during the acute period. The results suggest prolonged hyperactivation of the HPA axis and SAMS after IS. Specifically, post-stroke cognitive impairment was associated with hyperactivation of the HPA axis during the acute IS period, while post-stroke depressive disorder was associated with the chronic inflammatory process and hyperactivation of SAMS during the follow-up period.

Glial cell line-derived neurotrophic factor (GDNF) in patients with primary open-angle glaucoma and age-related cataract.

Purpose: To study glial cell line-derived neurotrophic factor (GDNF) concentrations in aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with age-related cataract and primary open-angle glaucoma (POAG). Methods: GDNF was studied in AH, LF, and BS in 47 patients with age-related cataract, and 30 patients with POAG combined with cataract (one eye in each person). AH was sampled during cataract surgery. Results: GDNF concentration (pg/ml) in patients with POAG and cataract was lower than in cataract-only patients (p<0.001), both in AH (46.3±31.1 versus 88.9±46.9) and in LF (222±101 versus 344±134). The difference was not significant for the GDNF concentration in BS (194±56 versus 201±45). In the earlier (early and moderate) stages of POAG, compared to later (advanced and severe) stages, GDNF concentration was significantly lower in LF (176±99 versus 258±91; p = 0.027) and in BS (165±42 versus 217±55; p = 0.017), while GDNF concentration in AH showed an insignificant difference (40.0±25.7 versus 51.1±34.7). In patients with POAG, GDNF concentration in LF and BS was inversely correlated with the Humphrey visual field index: Pearson's correlation coefficient r = -0.465 (p = 0.01) for LF and r = -0.399 (p = 0.029) for BS. When compared to the cataract group, patients in the earlier stages of POAG showed significantly lower GDNF concentrations in all studied biologic fluids. Conclusions: Compared to patients with cataract only, GDNF levels are lower in the AH and LF of patients with POAG and cataract, especially at earlier stages of the disease (at these stages, the GDNF level in BS is also lower). At earlier stages of POAG, compared to later stages, GDNF content is lower in LF and BS. These data could serve as a reason for the therapeutic use of GDNF in patients with POAG.

Elevated Serum Cortisol Levels in Patients with Focal Epilepsy, Depression, and Comorbid Epilepsy and Depression.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis, inflammatory processes and neurotrophic factor systems are involved in pathogenesis of both epilepsy and depressive disorders. The study aimed to explore these systems in patients with focal epilepsy (PWE, n = 76), epilepsy and comorbid depression (PWCED n = 48), and major depressive disorder (PWMDD, n = 62) compared with healthy controls (HC, n = 78). METHODS: Parameters of the HPA axis, neurotrophic factors, and TNF-α were measured in blood serum along with the hemogram. RESULTS: Serum cortisol level was augmented in PWE, PWCED, and PWMDD compared with HC and was higher in PWMDD than in PWE. Serum cortisol negatively correlated with Mini-Mental State Examination (MMSE) score in PWE, and positively with depression inventory-II (BDI-II) score in PWMDD. Only PWMDD demonstrated elevated plasma ACTH. Serum TNF-α, lymphocytes, and eosinophils were augmented in PWMDD; monocytes elevated in PWE and PWCED, while neutrophils were reduced in PWE and PWMDD. Serum BDNF was decreased in PWE and PWCED, CNTF was elevated in all groups of patients. In PWE, none of above indices depended on epilepsy etiology. CONCLUSIONS: The results confirm the involvement of HPA axis and inflammatory processes in pathogenesis of epilepsy and depression and provide new insights in mechanisms of epilepsy and depression comorbidity.

Does the inability of CA1 area to respond to ischemia with early rapid adenosine release contribute to hippocampal vulnerability?: An Editorial Highlight for "Spontaneous, transient adenosine release is not enhanced in the CA1 region of hippocampus during severe ischemia models".

This Editorial highlights a remarkable study in the current issue of the Journal of Neurochemistry in which Ganesana & Venton (2021) report new data showing that brain ischemia does not elicit transient adenosine release in the CA1 hippocampal area. Using fast-scan cyclic voltammetry at a carbon-fiber microelectrode implanted in the CA1 subfield of the hippocampus, it was shown that none of three different ischemia/reperfusion models could increase spontaneous, transient adenosine release, and more severe models even suppressed this presumably neuroprotective release. Since the authors have previously shown that in the caudate putamen, ischemia increased the frequency of spontaneous adenosine release (Ganesana & Venton, 2018), the new data may disclose a mechanism underlying important regional differences in rapid neuroprotective adenosine signaling. The phenomenon of selective susceptibility of the hippocampus to ischemia/hypoxia is well-documented, and the reported failure of its CA1 area to respond to ischemia by rapid adenosine release may be indicative of an insufficiency of this neuroprotective mechanism contributing to hippocampal vulnerability.

Hippocampal hyperglutamatergic signaling matters: Early targeting glutamate neurotransmission as a preventive strategy in Alzheimer's disease: An Editorial Highlight for "Riluzole attenuates glutamatergic tone and cognitive decline in AßPP/PS1 mice" on page 513.

This Editorial highlights a remarkable study in the current issue of the Journal of Neurochemistry in which Hascup and coworkers provide novel data showing that riluzole, an anti-glutamatergic drug, may be a promising early intervention strategy for Alzheimer's disease (AD), aimed at restoring glutamate neurotransmission prior to amyloid beta (Aß) plaque accumulation and cognitive decline. The mice APP/PS1, a model of AD, initially are cognitively normal but have elevated glutamate release in the hippocampus at 2-4 months of age. They begin showing cognitive decline and Aß plaque accumulation at approximately 6-8 months of age, and show obvious AD neuropathology and cognitive impairment at 10-12 months. The riluzole treatment over 4 months (at 2-6 months of age) targeting early changes in glutamatergic neurotransmission prevents cognitive decline observed at 12 months of age and restores glutamatergic neurotransmission. This is one of the most convincing preclinical evidence supporting the idea of targeting glutamate neurotransmission in patients at risk for AD and to use riluzole for this purpose.

Glucocorticoid-mediated mechanisms of hippocampal damage: Contribution of subgranular neurogenesis.

A comprehensive overview of the interplay between glucocorticoids (GCs) and adult hippocampal neurogenesis (AHN) is presented, particularly, in the context of a diseased brain. The effectors of GCs in the dentate gyrus neurogenic niche of the hippocampal are reviewed, and the consequences of the GC signaling on the generation and integration of new neurons are discussed. Recent findings demonstrating how GC signaling mediates impairments of the AHN in various brain pathologies are overviewed. GC-mediated effects on the generation and integration of adult-born neurons in the hippocampal dentate gyrus depend on the nature, severity, and duration of the acting stress factor. GCs realize their effects on the AHN primarily via specific glucocorticoid and mineralocorticoid receptors. Disruption of the reciprocal regulation between the hypothalamic-pituitary-adrenal (HPA) axis and the generation of the adult-born granular neurons is currently considered to be a key mechanism implicating the AHN into the pathogenesis of numerous brain diseases, including those without a direct hippocampal damage. These alterations vary from reduced proliferation of stem and progenitor cells to increased cell death and abnormalities in morphology, connectivity, and localization of young neurons. Although the involvement of the mutual regulation between the HPA axis and the AHN in the pathogenesis of cognitive deficits and mood impairments is evident, several unresolved critical issues are stated. Understanding the details of GC-mediated mechanisms involved in the alterations in AHN could enable the identification of molecular targets for ameliorating pathology-induced imbalance in the HPA axis/AHN mutual regulation to conquer cognitive and psychiatric disturbances.

Stress-Associated Molecular and Cellular Hippocampal Mechanisms Common for Epilepsy and Comorbid Depressive Disorders.

The review discusses molecular and cellular mechanisms common to the temporal lobe epileptogenesis/epilepsy and depressive disorders. Comorbid temporal lobe epilepsy and depression are associated with dysfunction of the hypothalamic-pituitary-adrenocortical axis. Excessive glucocorticoids disrupt the function and impair the structure of the hippocampus, a brain region key to learning, memory, and emotions. Selective vulnerability of the hippocampus to stress, mediated by the reception of glucocorticoid hormones secreted during stress, is the price of the high functional plasticity and pleiotropy of this limbic structure. Common molecular and cellular mechanisms include the dysfunction of glucocorticoid receptors, neurotransmitters, and neurotrophic factors, development of neuroinflammation, leading to neurodegeneration and loss of hippocampal neurons, as well as disturbances in neurogenesis in the subgranular neurogenic niche and formation of aberrant neural networks. These glucocorticoid-dependent processes underlie altered stress response and the development of chronic stress-induced comorbid pathologies, in particular, temporal lobe epilepsy and depressive disorders.

Changes in Gene Expression and Neuroinflammation in the Hippocampus after Focal Brain Ischemia: Involvement in the Long-Term Cognitive and Mental Disorders.

Ischemic brain injuries are accompanied by the long-term changes in gene expression in the hippocampus, the limbic system structure, involved in the regulation of key aspects of the higher nervous activity, such as cognitive functions and emotions. The altered expression of genes and proteins encoded by them may be related to the development of post-ischemic psycho-emotional and cognitive disturbances. Activation of neuroinflammation following stroke in the hippocampus has been suggested to play an essential role in induction of long-lasting consequences. Identification of changes in the gene expression patterns after ischemia and investigation of the dynamics of these changes in the hippocampus are the necessary first steps toward understanding molecular pathways responsible for the development of post-stroke cognitive impairments and mental pathologies.

Glucocorticoids: Dr. Jekyll and Mr. Hyde of Hippocampal Neuroinflammation.

Glucocorticoids (GCs) are an important component of adaptive response of an organism to stressogenic stimuli, a typical stress response being accompanied by elevation of GC levels in blood. Anti-inflammatory effects of GCs are widely used in clinical practice, while pro-inflammatory effects of GCs are believed to underlie neurodegeneration. This is particularly critical for the hippocampus, brain region controlling both cognitive function and emotions/affective behavior, and selectively vulnerable to neuroinflammation and neurodegeneration. The hippocampus is believed to be the main target of GCs since it has the highest density of GC receptors potentially underlying high sensitivity of hippocampal cells to severe stress. In this review, we analyzed the results of studies on pro- and anti-inflammatory effects of GCs in the hippocampus in different models of stress and stress-related pathologies. The available data form a sophisticated, though often quite phenomenological, picture of a modulatory role of GCs in hippocampal neuroinflammation. Understanding the dual nature of GC-mediated effects as well as causes and mechanisms of switching can provide us with effective approaches and tools to avert hippocampal neuroinflammatory events and as a result to prevent and treat brain diseases, both neurological and psychiatric. In the framework of a mechanistic view, we propose a new hypothesis describing how the anti-inflammatory effects of GCs may transform into the pro-inflammatory ones. According to it, long-term elevation of GC level or preliminary treatment with GC triggers accumulation of FKBP51 protein that suppresses activity of GC receptors and activates pro-inflammatory cascades, which, finally, leads to enhanced neuroinflammation.

Neonatal Proinflammatory Stress and Expression of Neuroinflammation-Associated Genes in the Rat Hippocampus.

Differential effect of the neonatal proinflammatory stress (NPS) on the development of neuroinflammation in the hippocampus and induction of the depressive-like behavior in juvenile and adult male and female rats was studied. NPS induction by bacterial lipopolysaccharide in the neonatal period upregulated expression of the Il6 and Tnf mRNAs accompanied by the development of depressive-like behavior in the adult male rats. NPS increased expression of the mRNAs for fractalkine and its receptor in the ventral hippocampus of the juvenile male rats, but did not affect expression of mRNAs for the proinflammatory cytokines and soluble form of fractalkine. NPS downregulated expression of fractalkine mRNA in the dorsal hippocampus of juvenile males. No significant effects of NPS were found in the female rats. Therefore, the NPS induces long-term changes in the expression of neuroinflammation-associated genes in different regions of the hippocampus, which ultimately leads to the induction of neuroinflammation and development of depressive-like behavior in male rats.

A Comparative Study of Koizumi and Longa Methods of Intraluminal Filament Middle Cerebral Artery Occlusion in Rats: Early Corticosterone and Inflammatory Response in the Hippocampus and Frontal Cortex.

Two classical surgical approaches for intraluminal filament middle cerebral artery occlusion (MCAO), the Longa et al. (LM) and Koizumi et al. methods (KM), are used as alternatives in preclinical studies to induce stroke in rodents. Comparisons of these MCAO models in mice showed critical differences between them along with similarities (Smith et al. 2015; Morris et al. 2016). In this study, a direct comparison of MCAO-KM and MCAO-LM in rats was performed. Three days after MCAO, infarct volume, mortality rate, neurological deficit, and weight loss were similar in these models. MCAO-LM rats showed an increase in ACTH levels, while MCAO-KM rats demonstrated elevated corticosterone and interleukin-1ß in blood serum. Corticosterone accumulation was detected in the frontal cortex (FC) and the hippocampus of the MCAO-KM group. IL1ß beta increased in the ipsilateral hippocampus in the MCAO-KM group and decreased in the contralateral FC of MCAO-LM rats. Differences revealed between MCAO-KM and MCAO-LM suggest that corticosterone and interleukin-1ß release as well as hippocampal accumulation is more expressed in MCAO-KM rats, predisposing them to corticosterone-dependent distant neuroinflammatory hippocampal damage. The differences between two models, particularly, malfunction of the hypothalamic-pituitary-adrenal axis, should be considered in the interpretation, comparison, and translation of pre-clinical experimental results.

Neuroinflammation and Neuronal Loss in the Hippocampus Are Associated with Immediate Posttraumatic Seizures and Corticosterone Elevation in Rats.

Hippocampal damage after traumatic brain injury (TBI) is associated with late posttraumatic conditions, such as depression, cognitive decline and epilepsy. Mechanisms of selective hippocampal damage after TBI are not well understood. In this study, using rat TBI model (lateral fluid percussion cortical injury), we assessed potential association of immediate posttraumatic seizures and changes in corticosterone (CS) levels with neuroinflammation and neuronal cell loss in the hippocampus. Indices of distant hippocampal damage (neurodegeneration and neuroinflammation) were assessed using histological analysis (Nissl staining, Iba-1 immunohistochemical staining) and ELISA (IL-1ß and CS) 1, 3, 7 and 14 days after TBI or sham operation in male Wistar rats (n = 146). IL-1ß was elevated only in the ipsilateral hippocampus on day 1 after trauma. CS peak was detected on day 3 in blood, the ipsilateral and contralateral hippocampus. Neuronal cell loss in the hippocampus was demonstrated bilaterally; in the ipsilateral hippocampus it started earlier than in the contralateral. Microglial activation was evident in the hippocampus bilaterally on day 7 after TBI. The duration of immediate seizures correlated with CS elevation, levels of IL-1ß and neuronal loss in the hippocampus. The data suggest potential association of immediate post-traumatic seizures with CS-dependent neuroinflammation-mediated distant hippocampal damage.

Functional Neurochemistry of the Ventral and Dorsal Hippocampus: Stress, Depression, Dementia and Remote Hippocampal Damage.

The hippocampus is not a homogeneous brain area, and the complex organization of this structure underlies its relevance and functional pleiotropism. The new data related to the involvement of the ventral hippocampus in the cognitive function, behavior, stress response and its association with brain pathology, in particular, depression, are analyzed with a focus on neuroplasticity, specializations of the intrinsic neuronal network, corticosteroid signaling through mineralocorticoid and glucocorticoid receptors and neuroinflammation in the hippocampus. The data on the septo-temporal hippicampal gradient are analyzed with particular emphasis on the ventral hippocampus, a region where most important alteration underlying depressive disorders occur. According to the recent data, the existing simple paradigm "learning (dorsal hippocampus) versus emotions (ventral hippocampus)" should be substantially revised and specified. A new hypothesis is suggested on the principal involvement of stress response mechanisms (including interaction of released glucocorticoids with hippocampal receptors and subsequent inflammatory events) in the remote hippocampal damage underlying delayed dementia and depression induced by focal brain damage (e.g. post-stroke and post-traumatic). The translational validity of this hypothesis comprising new approaches in preventing post-stroke and post-trauma depression and dementia can be confirmed in experimental and clinical studies.

Ciliary neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract.

Purpose: To study the ciliary neurotrophic factor (CNTF) concentration in the aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with age-related cataract and primary open-angle glaucoma (POAG). Methods: CNTF concentrations were studied in 61 patients with age-related cataract, 55 patients with POAG combined with cataract, and 29 healthy controls (one eye in each person). Preliminary experiments permitted us to extend the minimum quantifiable value of the CNTF Quantikine enzyme-linked immunosorbent assay (ELISA) kit to 2.5 pg/ml. Results: The levels of CNTF in LF and BS did not differ in patients with cataract and controls. The CNTF concentration (pg/ml) in patients with POAG and cataract was lower than in patients with cataract (p<0.001) in AH (39.9±26.2 versus 57.2±25.6) and in LF (25.7±14.9 versus 39.9±18.0). The differences were not statistically significant for the CNTF level in BS (5.45±4.72 versus 5.96±4.92) and the AH/LF ratio (1.69±1.05 versus 1.58±0.70). In the patients with POAG, the AH level of CNTF correlated with the visual field index (Pearson's correlation coefficient r = 0.35, p = 0.01). A statistically significant decrease in the AH and LF concentrations of CNTF was observed in patients in all stages of POAG compared with the cataract group. This decrease was particularly prominent in patients with severe glaucoma. Compared to patients with combined early and moderate stages of disease patients with advanced glaucoma showed an insignificant reduction in the median CNTF concentration in AH and LF. The serum CNTF concentration did not show any dependence on the glaucoma stage. The CNTF concentration in the AH strongly correlated with the CNTF concentration in the LF (r=0.71, p<0.000). A formula was suggested to calculate the concentration of CNTF in AH based on the CNTF concentration in LF. Conclusions: The CNTF concentration is reduced in the AH and LF of patients with POAG, especially in those with severe visual field loss. The CNTF concentration in AH and LF showed a strong correlation, and this phenomenon opens up new options for a noninvasive estimation of the CNTF concentration in AH. The CNTF concentration established in the AH, LF, and BS of patients with age-related cataract can serve as normative data for persons older than 50 years old.