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.

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.

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.

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.