Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic brain injury in rats

O'Connor, Christine; Černak, Ibolja; Johnson, Felicity; Vink, Robert

doi:10.1016/j.expneurol.2007.01.034

Cited by 93 publications

(68 citation statements)

References 44 publications

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“…38 Substantial neuronal cell damage is observed in the brain especially in the CA3 region of the hippocampus after CHI if the injury is severe enough (for example, 450 g × 2 m). 5,43,60 Our data that acute Cerebrolysin treatment starting 1 hour after CHI significantly decreases neuronal cell loss in the DG and CA3 support a neuroprotective effect of Cerebrolysin. Preclinical studies have shown that acute treatment with Cerebrolysin reduces cerebral infarction in rats after transient ischemia while delayed administration of Cerebrolysin promotes neurological functional recovery without reducing lesion volume.…”

Section: Discussionmentioning

confidence: 51%

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Zhang¹,

Chopp

Meng³

et al. 2013

JNS

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Object Cerebrolysin is a unique peptide preparation that mimics the action of neurotrophic factors. This study was designed to investigate the effects of acute treatment of experimental closed head injury (CHI) in rats with Cerebrolysin on neurological function. Methods Adult male Wistar rats (n = 60) were subjected to impact acceleration–induced CHI. Closed head injured rats received intraperitoneal injection of saline (n = 30) or Cerebrolysin (2.5 ml/kg, n = 30) starting 1 hour postinjury and administered once daily until they were killed (2 or 14 days after CHI). To evaluate functional outcome, the modified neurological severity score (mNSS), foot fault, adhesive removal, and Morris water maze (MWM) tests were performed. Animals were killed on Day 14 (n = 20) after injury, and their brains were removed and processed for measurement of neuronal cells, axonal damage, apoptosis, and neuroblasts. The remaining rats (n = 40) were killed 2 days postinjury to evaluate cerebral microvascular patency by fluorescein isothiocyanate (FITC)–dextran perfusion (n = 16) and to measure the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase–9 (MMP-9) by using real-time reverse transcriptase-polymerase chain reaction (RT-PCR, n = 8) and by immunohistochemical analysis (n = 16). Results At 14 days post-CHI, the Cerebrolysin treatment group exhibited significant improvements in functional outcomes (the adhesive removal, mNSS, foot-fault, and MWM tests), and significantly more neurons and neuroblasts were present in the dentate gyrus (DG) (p < 0.05) compared with the saline-treated group (p < 0.05). At 2 days post-CHI, the Cerebrolysin group exhibited a significantly higher percentage of phosphorylated neurofilament H (pNF-H)–positive staining area in the striatum (p < 0.05), a significant increase in the percentage of FITC-dextran perfused vessels in the brain cortex (p < 0.05), a significant increase in the number of VEGF-positive cells (p < 0.05), and a significant reduction in the MMP-9 staining area (p < 0.05) compared with the saline-treated group. There was no significant difference in mRNA levels of MMP-9 and VEGF in the hippocampus and cortex 48 hours postinjury between Cerebrolysin- and saline-treated rats that sustained CHI. Conclusions Acute Cerebrolysin treatment improves functional recovery in rats after CHI. Cerebrolysin is neuroprotective for CHI (increased neurons in the dentate gyrus and the CA3 regions of the hippocampus and increased neuroblasts in the dentate gyrus) and may preserve axonal integrity in the striatum (significantly increased percentage of pNF-H–positive tissue in the striatum). Reduction of MMP-9 and elevation of VEGF likely contribute to enhancement of vascular patency and integrity as well as neuronal survival induced by Cerebrolysin. These promising results suggest that Cerebrolysin may be a useful treatment in improving the recovery of patients with CHI.

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Section: Discussionmentioning

confidence: 51%

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Zhang¹,

Chopp

Meng³

et al. 2013

JNS

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“…In male and ovariectomized female rats with brain injury, treatment with progesterone improved their motor and cognitive performance with attenuation of caspase-3 immunoreactivity and reduction of axonal injury. 74 In the phase II ProTECT clinical study in 100 patients with acute TBI, treatment with progesterone was safe and a 30-day post-injury follow-up showed lower mortality. Also, moderate to good clinical outcome with improved GOS-E scores were observed in patients with moderate TBI (initial GCS 9 -12), but no differences were observed between progesterone treatment and placebo groups for patients with severe TBI.…”

Section: Clinical Studiesmentioning

confidence: 98%

Use of Magnesium in Traumatic Brain Injury

Sen¹,

Gulati

2010

Neurotherapeutics

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Summary: Depletion of magnesium is observed in animal brain and in human blood after brain injury. Treatment with magnesium attenuates the pathological and behavioral changes in rats with brain injury; however, the therapeutic effect of magnesium has not been consistently observed in humans with traumatic brain injury (TBI). Secondary brain insults are observed in patients with brain injury, which adversely affect clinical outcome. Systemic administration studies in rats have shown that magnesium enters the brain; however, inducing hypermagnesemia in humans did not concomitantly increase magnesium levels in the CSF. We hypothesize that the neuroprotective effects of magnesium in TBI patients could be observed by increasing its brain bioavailability with mannitol. Here, we review the role of magnesium in brain injury, preclinical studies in brain injury, clinical safety and efficacy studies in TBI patients, brain bioavailability studies in rat, and pharmacokinetic studies in humans with brain injury. Neurodegeneration after brain injury involves multiple biochemical pathways. Treatment with a single agent has often resulted in poor efficacy at a safe dose or toxicity at a therapeutic dose. A successful neuroprotective therapy needs to be aimed at homeostatic control of these pathways with multiple agents. Other pharmacological agents, such as dexanabinol and progesterone, and physiological interventions, with hypothermia and hyperoxia, have been studied for the treatment of brain injury. Treatment with magnesium and hypothermia has shown favorable outcome in rats with cerebral ischemia. We conclude that coadministration of magnesium and mannitol with pharmacological and physiological agents could be an effective neuroprotective regimen for the treatment of TBI.

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“…89 This inhibition of apoptosis may, in part, account for the reduced axonal damage observed in white matter after TBI following treatment with progesterone. 90 The fact that progesterone reduces inflammation after TBI 91 may also contribute to the widely observed beneficial effects of the hormone on edema. Administration of progesterone after brain injury attenuated edema in both female and male animals, 92,93 irrespective of estrogen.…”

Section: Progesteronementioning

confidence: 99%

Multifunctional Drugs for Head Injury

2009

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Summary: Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.

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Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic brain injury in rats

Cited by 93 publications

References 44 publications

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Use of Magnesium in Traumatic Brain Injury

Multifunctional Drugs for Head Injury

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