Dysautonomia and small fiber neuropathy in post-COVID condition and Chronic Fatigue Syndrome.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID condition can present similarities such as fatigue, brain fog, autonomic and neuropathic symptoms. METHODS: The study included 87 patients with post-COVID condition, 50 patients with ME/CFS, and 50 healthy controls (HC). The hemodynamic autonomic function was evaluated using the deep breathing technique, Valsalva maneuver, and Tilt test. The presence of autonomic and sensory small fiber neuropathy (SFN) was assessed with the Sudoscan and with heat and cold evoked potentials, respectively. Finally, a complete neuropsychological evaluation was performed. The objective of this study was to analyze and compare the autonomic and neuropathic symptoms in post-COVID condition with ME/CFS, and HC, as well as, analyze the relationship of these symptoms with cognition and fatigue. RESULTS: Statistically significant differences were found between groups in heart rate using the Kruskal-Wallis test (H), with ME/CFS group presenting the highest (H = 18.3; p ≤ .001). The Postural Orthostatic Tachycardia Syndrome (POTS), and pathological values in palms on the Sudoscan were found in 31% and 34% of ME/CFS, and 13.8% and 19.5% of post-COVID patients, respectively. Concerning evoked potentials, statistically significant differences were found in response latency to heat stimuli between groups (H = 23.6; p ≤ .01). Latency was highest in ME/CFS, and lowest in HC. Regarding cognition, lower parasympathetic activation was associated with worse cognitive performance. CONCLUSIONS: Both syndromes were characterized by inappropriate tachycardia at rest, with a high percentage of patients with POTS. The prolonged latencies for heat stimuli suggested damage to unmyelinated fibers. The higher proportion of patients with pathological results for upper extremities on the Sudoscan suggested a non-length-dependent SFN.

Brain fog of post-COVID-19 condition and Chronic Fatigue Syndrome, same medical disorder?

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is characterized by persistent physical and mental fatigue. The post-COVID-19 condition patients refer physical fatigue and cognitive impairment sequelae. Given the similarity between both conditions, could it be the same pathology with a different precipitating factor? OBJECTIVE: To describe the cognitive impairment, neuropsychiatric symptoms, and general symptomatology in both groups, to find out if it is the same pathology. As well as verify if the affectation of smell is related to cognitive deterioration in patients with post-COVID-19 condition. METHODS: The sample included 42 ME/CFS and 73 post-COVID-19 condition patients. Fatigue, sleep quality, anxiety and depressive symptoms, the frequency and severity of different symptoms, olfactory function and a wide range of cognitive domains were evaluated. RESULTS: Both syndromes are characterized by excessive physical fatigue, sleep problems and myalgia. Sustained attention and processing speed were impaired in 83.3% and 52.4% of ME/CFS patients while in post-COVID-19 condition were impaired in 56.2% and 41.4% of patients, respectively. Statistically significant differences were found in sustained attention and visuospatial ability, being the ME/CFS group who presented the worst performance. Physical problems and mood issues were the main variables correlating with cognitive performance in post-COVID-19 patients, while in ME/CFS it was anxiety symptoms and physical fatigue. CONCLUSIONS: The symptomatology and cognitive patterns were similar in both groups, with greater impairment in ME/CFS. This disease is characterized by greater physical and neuropsychiatric problems compared to post-COVID-19 condition. Likewise, we also propose the relevance of prolonged hyposmia as a possible marker of cognitive deterioration in patients with post-COVID-19.

The role of ketamine in major depressive disorders: Effects on parvalbumin-positive interneurons in hippocampus.

Major depressive disorder (MDD) is a complex illness that is arising as a growing public health concern. Although several brain areas are related to this type of disorders, at the cellular level, the parvalbumin-positive cells of the hippocampus interplay a very relevant role. They control pyramidal cell bursts, neuronal networks, basic microcircuit functions, and other complex neuronal tasks involved in mood disorders. In resistant depressions, the efficacy of current antidepressant treatments drops dramatically, so the new rapid-acting antidepressants (RAADs) are being postulated as novel treatments. Ketamine at subanesthetic doses and its derivative metabolites have been proposed as RAADs due to their rapid and sustained action by blocking N-methyl-d-aspartate (NMDA) receptors, which in turn lead to the release of brain-derived neurotrophic factor (BDNF). This mechanism produces a rapid plasticity activation mediated by neurotransmitter homeostasis, synapse recovery, and increased dendritic spines and therefore, it is a promising therapeutic approach to improve cognitive symptoms in MDD.

Effects of VEGF administration or neutralization on the BBB of developing rat brain.

We investigated the effects of exogenous Vascular Endothelial Growth Factor VEGF combined with an enriched environment on BBB integrity after a minimal trauma induced during the first days of the critical visual period in rats, when peak levels of endogenous VEGF secretion are reached. VEGF was administered using osmotic mini-pumps placed in middle cortical layers of P18 Long-Evansrats. Tissue changes were evaluated using conventional histology. BBB integrity was shown by immunohistochemistry techniques for EBA and GluT-1. Mini-pump implantation produced a wider cavity in anti-VEGF infused rats. In VEGF-infused rats there was a damaged region around the cannula that was smaller in rats raised in an enriched environment (EE). The administration of VEGF induced a high concentration of plasma proteins in the neuropil around the point of cannula placement and a high inflammatory reaction. VEGF-infused rats raised in an EE showed a lower degree of extravasation and better tissue preservation. Anti-VEGF administration produced a lower protein expression profile and more widespread deterioration of tissue. Double immunofluorescence for EBA and GluT-1 showed that the administration of VEGF preserves the tissue, which remains present but not fully functional. In contrast, a combination of VEGF administration and an EE partially protects the functionally damaged tissue with a higher preservation of BBB integrity.

The role of eNOS in vascular permeability in ENU-induced gliomas.

Brain edema in gliomas is an epiphenomenon related to blood-brain-barrier (BBB) breakdown in which endothelial nitric oxide synthase (eNOS) plays a key role. When induced by vascular endothelial growth factor (VEGF), eNOS synthesizes nitric oxide that increases vascular permeability. We investigated the relationship between eNOS, VEGF and BBB dysfunction in experimental gliomas.Tumors were produced in Sprague-Dawley rats by transplacentary administration of Ethylnitrosourea (ENU). Immunoexpression of eNOS and VEGF(165) was studied to identify locations of vascular permeability. BBB permeability was evaluated using gadolinium and intravital dyes and BBB integrity by endothelial barrier antigen (EBA), glucose transporter-1 (GluT-1) and occludin immunostaining. Low grade gliomas displayed constitutive eNOS expression in endothelial cells and in VEGF-positive astrocytes surrounding vessels. Malignant gliomas overexpressed eNOS in aberrant vessels and displayed numerous adjacent reactive astrocytes positive for VEGF. Huge dilated vessels inside tumors and glomeruloid vessels on the periphery of the tumor showed strong immunopositivity for eNOS and a lack of occludin and EBA staining in several vascular sections. BBB dysfunction on these aberrant vessels caused increased permeability as shown by Gadolinium contrast enhancement and intravital dye extravasation.These findings support the central role of eNOS in intra- and peritumoral edema in ENU-induced gliomas.

Deleterious Effects of VEGFR2 and RET Inhibition in a Preclinical Model of Parkinson's Disease.

Neurotrophic factors (NTFs) are a promising therapeutic option for Parkinson's disease (PD). They exert their function through tyrosine kinase receptors. Our goal was to assess the effects of administering a selective tyrosine kinase inhibitor (vandetanib) that blocks VEGFR2 and RET receptors in a preclinical model of PD. Rats underwent intrastriatal injections of 6-hydroxydopamine (6-OHDA). Two weeks later, the rats received 30 mg/kg vandetanib or saline orally. The effects were assessed using the rotational behavioral test, tyrosine hydroxylase (TH) immunohistochemistry, and western blot. In 6-OHDA-lesioned rats, motor symptoms were almost undetectable, but morphological and biochemical changes were significant. Vandetanib treatment, combined with the presence of 6-OHDA lesions, significantly increased behavioral impairment and morphological and biochemical changes. Therefore, after vandetanib treatment, the TH-immunopositive striatal volume, the percentage of TH+ neurons, and the extent of the axodendritic network in the substantia nigra decreased. Glial fibrillary acidic protein-positivity significantly decreased in the striatum and substantia nigra in the vandetanib-treated group. In addition, p-Akt and p-ERK 1/2 levels were significantly lower and caspase-3 expression significantly increased after vandetanib administration. In conclusion, we demonstrate for the first time the deleterious effect of a tyrosine kinase inhibitor on the dopaminergic system, supporting the beneficial and synergistic effect of NTFs reported in previous papers.

Correction to: Deleterious Effects of VEGFR2 and RET Inhibition in a Preclinical Model of Parkinson's Disease.

The authors found a terrible mistake in the manuscript. The legends from the Fig. 5 and 6 are interchanged. The Fig. 5 should be appeared with the legend from the Fig. 6 and Fig. 6 should be appeared with the legend from the Fig. 5.

Nanodelivery of Cerebrolysin and Rearing in Enriched Environment Induce Neuroprotective Effects in a Preclinical Rat Model of Parkinson's Disease.

Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO2-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL + EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL + EE group showed more significant number of laps in the wheel than EE group. In SN, CBL + EE group also presented the highest neuronal density. Moreover, p-Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL + EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD.

VEGF immunopositivity related to malignancy degree, proliferative activity and angiogenesis in ENU-induced gliomas.

Growth of solid tumors is highly dependent on angiogenesis. During tumor development, neoplastic cells switch to an angiogenic phenotype, playing a significant role in the expression of the vascular endothelial growth factor (VEGF). Seventy-two brain gliomas were induced in Sprague Dawley rats by prenatal exposure to ethylnitrosourea (ENU). Screening and location of tumors was carried out using magnetic resonance imaging (MRI). Conventional histology and immunocytochemistry for antibodies against glial fibrillary acidic protein (GFAP), S-100, NF, oligodendrocyte Ab-2, Ki-67, and VEGF165 were performed. The proliferation index (PI) was calculated from the Ki-67 labeling index, and the concentration of VEGF165 was quantified by enzyme-linked immunosorbent assay (ELISA). In vivo identification of macro- and microtumor appears to be useful to lead morphological and biochemical studies. Histopathology allows us to identify microtumors as classic oligodendrogliomas (CO; mean PI of 6.01 +/- 2.8%) and macrotumors as anaplastic oligodendrogliomas (AO; mean PI of 14.06 +/- 5%). Classic oligodendrogliomas show scarce VEGF165 expression whereas anaplastic ones display VEGF165 protein level 100-fold increased respect to CO. Astrocytes, neoplastic, and endothelial cells show differential immunostaining patterns from the border to the core of neoplasm. Positive structures for VEGF and their distribution vary according to PI increase. Anaplastic gliomas displaying VEGF-positive intratumor capillaries correspond to the highest PI values. To identify the "angiogenic switch," we propose the glioma stage characterized by VEGF immunopositive neoplastic cells inside the tumor and positive endothelial cells surrounding it.

Morphological Changes in a Severe Model of Parkinson's Disease and Its Suitability to Test the Therapeutic Effects of Microencapsulated Neurotrophic Factors.

The unilateral 6-hydroxydopamine (6-OHDA) lesion of medial forebrain bundle (MFB) in rats affords us to study the advanced stages of Parkinson's disease (PD). Numerous evidences suggest synergic effects when various neurotrophic factors are administered in experimental models of PD. The aim of the present work was to assess the morphological changes along the rostro-caudal axis of caudo-putamen complex and substantia nigra (SN) in the referred model in order to test the suitability of a severe model to evaluate new neurorestorative therapies. Administration of 6-OHDA into MFB in addition to a remarkable depletion of dopamine in the nigrostriatal system induced an increase of glial fibrillary acidic protein (GFAP)-positive cells in SN and an intense immunoreactivity for OX-42, vascular endothelial growth factor (VEGF), and Lycopersycum esculentum agglutinin (LEA) in striatum and SN. Tyrosine hydroxylase (TH) immunostaining revealed a significant decrease of the TH-immunopositive striatal volume in 6-OHDA group from rostral to caudal one. The loss of TH-immunoreactive (TH-ir) neurons and axodendritic network (ADN) was higher in caudal sections. Morphological recovery after the implantation of microspheres loaded with VEGF and glial cell line-derived neurotrophic factor (GDNF) in parkinsonized rats was related to the preservation of the TH-ir cell number and ADN in the caudal region of the SN. In addition, these findings support the neurorestorative role of VEGF+GDNF in the dopaminergic system and the synergistic effect between both factors. On the other hand, a topological distribution of the dopaminergic system was noticeable in the severe model, showing a selective vulnerability to 6-OHDA and recovering after treatment.

Intranasal Administration of chitosan-Coated Nanostructured Lipid Carriers Loaded with GDNF Improves Behavioral and Histological Recovery in a Partial Lesion Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, but current therapies are only symptomatic. A promising alternative to address the neurodegenerative process is the use of neurotrophic factors, such as the glial cell-derived neurotrophic factor (GDNF). However, its clinical use has been limited due to its short half-life and rapid degradation after in vivo administration, in addition to difficulties in crossing the blood-brain barrier (BBB). This barrier is a limiting factor in brain drug development, making the future progression of neurotherapeutics difficult. In the past few years, intranasal drug delivery has appeared as an alternative non-invasive administration route to bypass the BBB and target drugs directly to the CNS. Thus, the aim of this work was to study the in vivo neuroprotective effect of intranasally administered GDNF, encapsulated in chitosan-coated nanostructured lipid carrier (CS-NLC-GDNF), in a 6-OHDA partially lesioned rat model. The developed CS-NLC-GDNF showed a particle size of approximately 130 nm and high encapsulation efficiency. The in vitro study in PC-12 cells demonstrated the ability of the encapsulated GDNF to protect these cells against 6-OHDA toxin. After two weeks of daily intranasal administration of treatments, the administration of CS-NLC-GDNF achieved a behavioral improvement in rats, as well as a significant improvement in both the density of TH+ fibres in the striatum and the TH+ neuronal density in the SN. Thus, it can be concluded that the nose-to-brain delivery of CS-NLC-GDNF could be a promising therapy for the treatment of PD.

Topographical Distribution of Morphological Changes in a Partial Model of Parkinson's Disease--Effects of Nanoencapsulated Neurotrophic Factors Administration.

Administration of various neurotrophic factors is a promising strategy against Parkinson's disease (PD). An intrastriatal infusion of 6-hydroxidopamine (6-OHDA) in rats is a suitable model to study PD. This work aims to describe stereological parameters regarding rostro-caudal gradient, in order to characterize the model and verify its suitability for elucidating the benefits of therapeutic strategies. Administration of 6-OHDA induced a reduction in tyrosine hidroxylase (TH) reactivity in the dorsolateral part of the striatum, being higher in the caudal section than in the rostral one. Loss of TH-positive neurons and axodendritic network was highly significant in the external third of substantia nigra (e-SN) in the 6-OHDA group versus the saline one. After the administration of nanospheres loaded with neurotrophic factors (NTF: vascular endothelial growth factor (VEGF) + glial cell line-derived neurotrophic factor (GDNF)), parkinsonized rats showed more TH-positive fibers than those of control groups; this recovery taking place chiefly in the rostral sections. Neuronal density and axodendritic network in e-SN was more significant than in the entire SN; the topographical analysis showed that the highest difference between NTF versus control group was attained in the middle section. A high number of bromodeoxyuridine (BrdU)-positive cells were found in sub- and periventricular areas in the group receiving NTF, where most of them co-expressed doublecortin. Measurements on the e-SN achieved more specific and significant results than in the entire SN. This difference in rostro-caudal gradients underpins the usefulness of a topological approach to the assessment of the lesion and therapeutic strategies. Findings confirmed the neurorestorative, neurogenic, and synergistic effects of VEGF+GDNF administration.

Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor-beta (PDGFR-beta) in human gliomas.

The growth of solid tumors is highly dependent on vascular proliferation. Vascular endothelial growth factor (VEGF), the main mediator of angiogenesis, and platelet-derived growth factor receptor-beta (PDGFR-beta), receptor for the potent mitogen PDGF, are two indicators of the angiogenic potential of human gliomas. We studied a series of 57 surgical biopsies of astrocytic neoplasms by immunohistochemistry to elucidate the relationship between tumor proliferation, quantified as Ki67-LI, and the expression of these two proteins. Ki67-LI increases throughout histological malignancy, although staining in endothelial cells has rarely been recorded. Elevated amounts of VEGF-positive tumor cells (VEGF-LI) were found in anaplastic astrocytomas and glioblastomas, mainly around areas of necrosis, cysts, or edema. Endothelium of blood vessels was consistently stained. PDGFR-beta positivity was found in glomeruloid formations and in tumor cells, excluding pilocytic astrocytomas. Multinucleated giant cells and perivascular tumor cells were positive in glioblastomas. In addition, peritumoral microglia-like cells were also stained in some cases. Statistical correlation was only found between PDGFR-beta and Ki67 LIs. In conclusion, VEGF as permeability factor is involved in the development of secondary neoplastic changes, whereas PDGFR-beta is directly correlated to proliferation indexes. Strong expression of VEGF and PDGFR-beta found in endothelium and tumor cells would seem to support a combined role in tumoral neoangiogenesis.

Craniocerebral trauma induces hemorheological disturbances.

Several mechanisms are involved in the development of secondary ischemic brain damage, including microthrombi formation, which is thought to play a prominent role. Ninety-four autopsy cases were macro- and microscopically examined by specific staining for fibrin, 74 of which showed cortical contusion after a craniocerebral trauma. Twenty cases with no neurological pathology were used as controls. Traumatic cases comprised 52 males and 22 females, with a mean age of 48 years; most cases died in the first 48 h. The total number of fibrinous microthrombi in a slice of each hemisphere was determined. The mean number of microthrombi found in contused hemisphere was 152 (37-283), with 88 in the contralateral hemisphere (21-139) as compared to 13 (0-27) in control cases. Differences were statistically significant. Globular microthrombi or "shock bodies" (2-60 micro diameter) were present in five cases. Enhanced presence of microthrombi in contused brain areas, higher incidence in young people, an increase in the amount of microthrombi up to the 9th day after injury and involvement of the contralateral hemisphere free of contusion foci were all demonstrated. Microthrombi would therefore seem to be one of the central secondary events after brain trauma to bear in mind when designing treatment strategies.

Effects of dark-rearing on the vascularization of the developmental rat visual cortex.

Cerebral vascular density corresponds to metabolic demand, which increases in highly active areas. External inputs play an important role in the modeling and development of the visual cortex. Experience-mediated development is very active during the first postnatal month, when accurate simultaneous blood supply is needed to satisfy increased demand. We studied the development of visual cortex vascularization in relation to experience, comparing rats raised in darkness with rats raised in standard conditions. The parameters measured were cortical thickness, vascular density and number of perpendicular vessels, constituting the first stage of cortical vascular development. Vessels were stained using butyryl cholinesterase histochemistry, which labels some neurons and microvascularization (vessels from 5 to 50 microns). Animals from both groups were sampled at 0, 7, 14, 21 and 60 days postnatal. Vascularization of the brain starts with vertically oriented intracortical vascular trunks whose density decreases notably after birth in rats reared in standard laboratory conditions. The most striking finding of our work is the significantly lower decrease in the number of these vessels in dark-reared rats. Our results also show that cortex thickness and vessel density are significantly lower in dark-reared rats. These results suggest that the absence of visual stimuli retards the maturation of the visual cortex including its vascular bed.

Influence of visual experience deprivation on the postnatal development of the microvascular bed in layer IV of the rat visual cortex.

Cerebral vascular density is correlated with metabolic demands, which increase in highly active brain areas. External inputs are an essential requirement in the modeling of the visual cortex. Experience-mediated development is very active during the first postnatal month, when congruous blood supply is needed. We studied the development of visual cortex vascularization in relation to experience, comparing rats raised in darkness with rats reared in normal conditions. Vascular density, vascular area and their ratio vs. neuronal density were calculated. Conventionally stained semi-thin sections were used to measure the vascular area by computer assisted morphometry. Animals from both groups were sampled at 14, 21, and 60 days postnatal (dpn). We found a significantly lower density of vessels and neurons as well as a smaller vascular area in dark-reared adult rats while no differences were founded at the other ages. Our results also show no differences between the ratio of vessels/neuron, and vascular area/neuron, between both groups. The absence of visual experience causes decrease of cortical activity which correlates with lower vessels density and vascular area, without their ratio/neuron being affected.

Traumatic brain injuries: structural changes.

A host of complications and consequences may follow a contusion or other brain injury of any sort. An appreciation of the temporal evolution of the contusion from a microscopic standpoint is useful to a full understanding of the process by which physical force damages the brain and how the brain reacts to this damage. Some disruptions of the blood brain barrier quite early will result in extracellular edema. The microscopic appearance of an edematous area is usually spongy with numerous vacuoles. The neuropil may appear bubbly, and glial cells may be swollen. If edema has been long standing, the vacuoles may be larger and in fact a small cyst may appear in the white matter. If focal cerebral edema is not present for long periods of time and the underlying cause has been corrected, residual fluid and electrolytes are eventually removed, restoring the neuropil to a normal state, leaving no sign of its presence. However, in longer standing lesions, myelin pallor and some reactive gliosis may remain indefinitely. Neurons may show swelling very early and for a short period of time, which gives way to shrinkage, eosinophilia, and nuclear pyknosis. These changes may be observed at the periphery of lesions for as long as 5 or 6 months after the initial event. Before dissolution, nuclear pyknosis may remain in the tissue for many days and possibly longer, and may even become mineralized in situ (ferruginated neurons) to remain for years. In a traumatic lesion, swollen and ballooned axons may be found in and around the contusion but also at great distances from it (diffuse axonal injury). Axonal ballooning may be observed between 24 and 48 h postinjury and may persist wherever found for many years. Selective axonal calcification has been observed in humans as well as in experimental trauma. At about 7-10 days postinjury increased numbers of astroglia probably are present. Over the ensuing weeks and months, and probably years, astrocytes increase in number and in fibrillary appearance, eventually resulting in a glial scar in and about the injured area. It is thought that this reactive gliosis results in restoration of the blood-brain barrier in the damaged area.

Pelizaeus-Merzbacher disease with thiamine deficiency or Leigh disease with extensive involvement of white matter? Case report.

We report on a case of a 30-month-old child who presented with a clinical syndrome compatible with leucodystrophy and in whom neuropathological features of both Pelizaeus-Merzbacher disease and subacute necrotizing encephalopathy were shown. The significance of the neuropathological findings is discussed in the light of a possible coexistence of both diseases which has not previously been reported.

Effects of chronic deep hypoxia on the expression of nitric oxide synthase in the rat brain.

Experimental studies in extreme hypoxic conditions affecting the brain have been performed mainly in acute but not chronic models. Twenty rats were housed and exposed to decreasing concentrations of oxygen (from 21% to 7% over 130 days) and ten normal rats were used as control. Paraffin slices from representative sections containing cerebral cortex, cerebellum, striatum, hippocampus, thalamus and hypothalamus were incubated with antisera against nitric oxide synthase. Cortex and striatum showed small randomly distributed positive neurons with bipolar features, in greater numbers in the hypoxic group (p < 0.02). The granular layer of the cerebellum showed a strongly positive rim around some cell nuclei. Purkinje cells were immunopositive in hypoxic rats. Hipoccampal, thalamic and hypothalamic nuclei showed no quantitative differences in the number of positive neurons. The increased number of blood vessels and their dilation observed in some brain regions in hypoxic rats, mainly in ventral striatum, lead us to hypothesise that NOS may be overexpressed and act at these sites as vasomodulator and/or mediator of secondary cell injury affecting selective neuronal populations. We conclude that prolonged periods of adaptation to deep hypoxia reduces the effect of hypoxia on the upregulation of NOS in the brain tissue.

[Biopathology of craniocerebral injuries: experimental models]. / Biopatología de los traumatismos craneoencefálicos: modelos experimentales.

INTRODUCTION: In traumatic brain injury the secondary damage is responsible for the majority of the clinical and pathological sequels. This circumstance together with the difficulties of acquiring well preserved brain material for specialized neuropathological study impair the understanding of processes implied in their pathophysiology. DEVELOPMENT AND CONCLUSIONS: The development of experimental models has played an outstanding role for the better knowledge of these processes. For the development of standardized experimental models the biophysical and anatomical characteristics of brain and skull of the various utilized species have to be considered, but the physiological, neurochemical and molecular peculiarities must also be taken into account. Various in vivo models have been developed, inducing direct impact to the skull or to the brain, or mimicking lesions subsequent to craniocerebral trauma, such as subarachnoid hemorrhage, hematoma or necrosis. To analyze the molecular mechanisms of cellular response in vitro models have been developed. A great amount of cells in the contusional area die immediately following traumatic brain injury, but a still higher number of cells will undergo in the following hours. This second wave of neuronal death is induced by phenomena such as secondary axotomy and brain edema. In the pathogenesis of both the damage of cytoplasmic membrane is involved.