Efficacy of early versus delayed spinal cord decompression in neurological recovery after traumatic spinal cord injury: Systematic review and meta-analysis. / Eficacia de la descompresión medular precoz versus tardía en la recuperación neurológica tras lesión medular traumática. Revisión sistemática y metaanálisis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To compare early (<24 h) versus late (>24 h) spinal cord decompression on neurological recovery in patients with acute spinal cord injury. METHODS: A systematic review was performed according to the PRISMA protocol to identify studies published up to December 2022. PROSPECTIVE: cohort studies and controlled trials comparing early versus delayed decompression on neurological recovery were included. Variables included number of patients, level of injury, treatment time, ASIA grade, neurological recovery, use of corticosteroids, and complications. For the meta-analysis, the «forest plot¼ graph was developed. The risk of bias of the included studies was assessed using the ROBINS-I22 and Rob223 tools. RESULTS: Six of the seven studies selected for our review were included in the meta-analysis, with a total of 1188 patients (592 patients in the early decompression group and 596 in the delayed decompression group), the mean follow-up was 8 months, in 5 studies used methylprednisolone, the most reported complications were thromboembolic cardiopulmonary events.Five studies showed significant differences in favour of early decompression (risk difference 0.10, 95% confidence interval 0.07-0.14, heterogeneity 46%). The benefit was greatest in cervical and incomplete injuries. CONCLUSION: There is scientific evidence to recommend early decompression in the first 24 h after traumatic spinal cord injury, as it improves final neurological recovery, and it should be recommended whenever the patient and hospital conditions allow it to be safely done.

Efficacy of early versus delayed spinal cord decompression in neurological recovery after traumatic spinal cord injury: Systematic review and meta-analysis. / Eficacia de la descompresión medular precoz versus tardía en la recuperación neurológica tras lesión medular traumática. Revisión sistemática y metaanálisis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To compare early (<24h) versus late (>24h) spinal cord decompression on neurological recovery in patients with acute spinal cord injury. METHODS: A systematic review was performed according to the PRISMA protocol to identify studies published up to December 2022. Prospective cohort studies and controlled trials comparing early versus delayed decompression on neurological recovery were included. Variables included number of patients, level of injury, treatment time, ASIA grade, neurological recovery, use of corticosteroids, and complications. For the meta-analysis, the «forest plot¼ graph was developed. The risk of bias of the included studies was assessed using the ROBINS-I22 and Rob223 tools. RESULTS: Six of the seven studies selected for our review were included in the meta-analysis, with a total of 1188 patients (592 patients in the early decompression group and 596 in the delayed decompression group), the mean follow-up was 8 months, in 5 studies used methylprednisolone, the most reported complications were thromboembolic cardiopulmonary events. Five studies showed significant differences in favor of early decompression (risk difference 0.10, 95% confidence interval 0.07-0.14, heterogeneity 46%). The benefit was greatest in cervical and incomplete injuries. CONCLUSION: There is scientific evidence to recommend early decompression in the first 24h after traumatic spinal cord injury, as it improves final neurological recovery, and it should be recommended whenever the patient and hospital conditions allow it to be safely done.

Mineralocorticoid receptor associates with pro-inflammatory bias in the hippocampus of spontaneously hypertensive rats.

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry. We also measured serum-glucocorticoid-activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, as well as mRNA expression levels of the pro-inflammatory factors cyclo-oxygenase 2 (Cox2), Nlrp3 inflammasome and tumour necrosis factor α (Tnfα). Expression of anti-inflammatory transforming growth factor (Tgf)ß mRNA and the NADPH-diaphorase activity of nitric oxide synthase (NOS) were also determined. The results showed that, in the hippocampus of SHR rats, expression of MR and the number of immunoreactive MR/GR co-expressing cells were increased compared to Wistar-Kyoto control animals. Expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ were also increased, whereas Tgfß mRNA expression and the NADPH-diaphorase activity of NOS were decreased. We propose that, in the SHR hippocampus, increased MR expression causes a bias towards a pro-inflammatory phenotype characteristic for hypertensive encephalopathy.

Selective Oestrogen Receptor Agonists Rescued Hippocampus Parameters in Male Spontaneously Hypertensive Rats.

Spontaneously hypertensive rats (SHR) show pronounced hippocampus alterations, including low brain-derived neurotrophic factor (BDNF) expression, reduced neurogenesis, astrogliosis and increased aromatase expression. These changes are reverted by treatment with 17ß-oestradiol. To determine which oestradiol receptor (ER) type is involved in these neuroprotective effects, we used agonists of the ERα [propylpyrazole triol (PPT)] and the ERß [diarylpropionitrite (DPN)] given over 2 weeks to 4-month-old male SHR. Wistar Kyoto normotensive rats served as controls. Using immunocytochemistry, we determined glial fibrillary protein (GFAP)+ astrocytes in the CA1, CA3 and hilus of the dentate gyrus of the hippocampus, aromatase immunostaining in the hilus, and doublecortin (DCX)+ neuronal progenitors in the inner granular zone of the dentate gyrus. Brain-derived neurotrophic factor mRNA was also measured in the hippocampus by the quantitative polymerase chain reaction. In SHR, PPT had no effect on blood pressure, decreased astrogliosis, slightly increased BDNF mRNA, had no effect on the number of DCX+ progenitors, and increased aromatase staining. Treatment with DPN decreased blood pressure, decreased astrogliosis, increased BDNF mRNA and DCX+ progenitors, and did not modify aromatase staining. We hypothesise that, although both receptor types may participate in the previously reported beneficial effects of 17ß-oestradiol in SHR, receptor activation with DPN may preferentially facilitate BDNF mRNA expression and neurogenesis. The results of the present study may help in the design of ER-based neuroprotection for the encephalopathy of hypertension.

Effects of 17ß-estradiol on the cytoarchitecture of pyramidal CA1 neurons in normoglycemic and diabetic male spontaneously hypertensive rats.

Previous work has shown a reduction of apical dendritic length and spine density in neurons from the CA1 hippocampus subfield of spontaneously hypertensive rats (SHRs). These abnormalities are prevented by treatment for 2 weeks with 17ß-estradiol. In view of the fact that diabetes and hypertension are comorbid diseases, we have now studied the effect of Streptozotocin-induced diabetes on the dendritic tree and spines of CA1 hippocampus neurons, and also compared the regulation of these parameters by 17ß-estradiol in diabetic and normoglycemic SHR. Twenty-week-old male SHR received i.v. 40-mg/kg Streptozotocin or vehicle and studied 1 month afterward. A group of normoglycemic and hyperglycemic SHR also received s.c. a single 17ß-estradiol pellet or vehicle for 2weeks. Hippocampus sections were impregnated with silver nitrate following a modified Golgi's method and the arbor of CA1 pyramidal neurons analyzed by Sholl's method. 17ß-Estradiol treatment of normoglycemic SHR reversed the reduced length of apical dendrites, the low spine density and additionally decreased blood pressure (BP). Diabetic SHR showed increased length of apical and basal dendrites but reduced spine density compared to normoglycemic SHR. Diabetes also decreased BP of SHR. Treatment with 17ß-estradiol of diabetic SHR enhanced dendritic length, increased dendritic spine density and further decreased BP. Thus, changes of cytoarchitecture of CA1 neurons due to 17ß-estradiol treatment of normoglycemic SHR persisted after diabetes induction. A decrease of BP may also contribute to the central effects of 17ß-estradiol in SHR diabetic rats.

17α-Oestradiol-induced neuroprotection in the brain of spontaneously hypertensive rats.

17ß-oestradiol is a powerful neuroprotective factor for the brain abnormalities of spontaneously hypertensive rats (SHR). 17α-Oestradiol, a nonfeminising isomer showing low affinity for oestrogen receptors, is also endowed with neuroprotective effects in vivo and in vitro. We therefore investigated whether treatment with 17α-oestradiol prevented pathological changes of the hippocampus and hypothalamus of SHR. We used 20-week-old male SHR with a blood pressure of approximately 170 mmHg receiving s.c. a single 800 µg pellet of 17α-oestradiol dissolved in cholesterol or vehicle only for 2 weeks Normotensive Wistar-Kyoto (WKY) rats were used as controls. 17α-Oestradiol did not modify blood pressure, serum prolactin, 17ß-oestradiol levels or the weight of the testis and pituitary of SHR. In the brain, we analysed steroid effects on hippocampus Ki67+ proliferating cells, doublecortin (DCX) positive neuroblasts, glial fibrillary acidic protein (GFAP)+ astrocyte density, aromatase immunostaining and brain-derived neurotrophic factor (BDNF) mRNA. In the hypothalamus, we determined arginine vasopressin (AVP) mRNA. Treatment of SHR with 17α-oestradiol enhanced the number of Ki67+ in the subgranular zone and DCX+ cells in the inner granule cell layer of the dentate gyrus, increased BDNF mRNA in the CA1 region and gyrus dentatus, decreased GFAP+ astrogliosis in the CA1 subfield, and decreased hypothalamic AVP mRNA. Aromatase expression was unmodified. By contrast to SHR, normotensive WKY rats were unresponsive to 17α-oestradiol. These data indicate a role for 17α-oestradiol as a protective factor for the treatment of hypertensive encephalopathy. Furthermore, 17α-oestradiol is weakly oestrogenic in the periphery and can be used in males.

Progesterone down-regulates spinal cord inflammatory mediators and increases myelination in experimental autoimmune encephalomyelitis.

In mice with experimental autoimmune encephalomyelitis (EAE) pretreatment with progesterone improves clinical signs and decreases the loss of myelin basic protein (MBP) and proteolipid protein (PLP) measured by immunohistochemistry and in situ hybridization. Presently, we analyzed if progesterone effects in the spinal cord of EAE mice involved the decreased transcription of local inflammatory mediators and the increased transcription of myelin proteins and myelin transcription factors. C57Bl/6 female mice were divided into controls, EAE and EAE receiving progesterone (100mg implant) 7 days before EAE induction. Tissues were collected on day 17 post-immunization. Real time PCR technology demonstrated that progesterone blocked the EAE-induced increase of the proinflammatory mediators tumor necrosis factor alpha (TNFα) and its receptor TNFR1, the microglial marker CD11b and toll-like receptor 4 (TLR4) mRNAs, and increased mRNA expression of PLP and MBP, the myelin transcription factors NKx2.2 and Olig1 and enhanced CC1+oligodendrocyte density respect of untreated EAE mice. Immunocytochemistry demonstrated decreased Iba1+microglial cells. Confocal microscopy demonstrated that TNFα colocalized with glial-fibrillary acidic protein+astrocytes and OX-42+microglial cells. Therefore, progesterone treatment improved the clinical signs of EAE, decreased inflammatory glial reactivity and increased myelination. Data suggest that progesterone neuroprotection involves the modulation of transcriptional events in the spinal cord of EAE mice.

Neuroprotection and sex steroid hormones: evidence of estradiol-mediated protection in hypertensive encephalopathy.

Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension. Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the spontaneously hypertensive rat (SHR). In the dentate gyrus of the hippocampus, SHR present decreased neurogenesis, astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus and increased basal levels of the estrogen-synthesizing enzyme aromatase, with respect to the Wistar Kyoto (WKY) normotensive strain. In the hypothalamus, SHR show increased expression of the hypertensinogenic peptide arginine vasopressin (AVP) and its V1b receptor. From the therapeutic point of view, it was highly rewarding that estradiol treatment decreased blood pressure and attenuated brain abnormalities of SHR, rendering hypertension a suitable model to test estrogen neuroprotection. When estradiol treatment was given for 2 weeks, SHR normalized their faulty brain parameters. This was shown by the enhancement of neurogenesis in the dentate gyrus, according to increased bromodeoxyuridine incorporation and doublecortin labeling, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus, increased neuronal number in the hilus of the dentate gyrus and a further hyperexpression of aromatase. The presence of estradiol receptors in hippocampus and hypothalamus suggests the possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive rats should encourage the treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated diseases.

Increased expression of the mineralocorticoid receptor in the brain of spontaneously hypertensive rats.

The mineralocorticoid receptor (MR) has been considered as both neuroprotective and damaging to the function of the central nervous system. MR may be also involved in central regulation of blood pressure. In the present study, we compared the expression of MR and the glucocorticoid receptor (GR) in the hippocampus and hypothalamus of 16-week-old spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats. In the hippocampus, MR expression was studied by in situ hybridization (ISH), quantitative polymerase chain reaction (PCR) and immunohistochemistry, whereas GR expression was analysed using the latter two procedures. Hypertensive animals showed an increased expression of MR mRNA in the whole hippocampus according to qPCR data and also in CA3 by ISH. Immunocytochemical staining for MR of the dorsal hippocampus, however, did not reveal differences between SHR and WKY rats. SHR showed elevated hypothalamic MR mRNA by qPCR, as well as an increased number of MR immunopositive cells in the magnocellular paraventricular region, compared to WKY rats. By contrast, expression levels of GR mRNA or protein in the hippocampus and hypothalamus of SHR were similar to those of WKY rats. Furthermore, we investigated the role of MR in the hypertensive rats by i.c.v. injection of the MR antagonist RU-2831. This compound produced a significant drop in blood pressure for SHR. In conclusion, MR expression is increased in the hippocampus and hypothalamus of SHR. We suggest that pathological MR overdrive may take responsibility for up-regulation of blood pressure and the encephalopathy of hypertension.

Increased aromatase expression in the hippocampus of spontaneously hypertensive rats: effects of estradiol administration.

There is high incidence of hippocampal abnormalities in spontaneously hypertensive rats (SHR), including decreased neurogenesis in the dentate gyrus, astrogliosis, low expression of brain derived neurotrophic factor and decreased neuronal density in the hilar region, respect of normotensive Wistar Kyoto rats (WKY). Estradiol treatment given for 2 weeks normalized the faulty hippocampal parameters of SHR, without having effects on WKY rats. The present work studied the potential role of local estrogen biosynthesis in the hippocampus of SHR and WKY, by measuring the expression of aromatase, the key enzyme responsible for estrogen biosynthesis and involved in neuroprotection. We used 4 month old male SHR and WKY, half of which received a single sc pellet of 12 mg estradiol benzoate and the remaining half a cholesterol implant. Hippocampi were dissected and processed for aromatase mRNA expression using real time PCR. A second batch of animals was processed for aromatase and glial fibrillary acidic protein (GFAP) immunocytochemistry. Basal level of aromatase mRNA was higher in SHR respect of WKY. Following estradiol treatment, aromatase mRNA was further increased in the SHR group only. In the hilus of the dentate gyrus of cholesterol-implanted SHR, we found aromatase immunoreactive cell processes and fibers more strongly stained respect of WKY rats. Estradiol treatment of SHR further increased the length of immunoreactive processes and fibers in the hilar region and also increased aromatase immunoreactivity in the CA1 but not the CA3 pyramidal cell region. WKY rats were spared from the estradiol effect. Double-labelling experiments showed that aromatase+ processes and fibers of the hilus of SHR-treated rats did no colocalize with GFAP+ astrocyte cell bodies or processes. In conclusion, basal and estradiol-stimulated aromatase expression was enhanced in hypertensive rat hippocampus. A combination of exogenous estrogens and those locally synthesized may better alleviate hypertensive encephalopathy.