2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

Abstract

HIF-1a is pivotal for cellular homeostasis in response to cerebral ischemia. Pharmacological inhibition of HIF-1a may reduce secondary brain damage by targeting post-translational mechanisms associated with its proteasomal degradation and nuclear translocation. This study examined the neuroprotective effects of 2-methoxyestradiol (2ME2), the involved HIF-1a-dependent response, and alternative splicing in exon 14 of HIF-1a (HIF-1aΔEx14) after traumatic brain injury (TBI) in mice. Intraperitoneal 2ME2 administration 30 min after TBI caused a dose-dependent reduction in secondary brain damage after 24 h. 2ME2 was physiologically tolerated, showed no effects on immune cell brain migration, and mitigated trauma-induced brain expression of neuropathologically relevant HIF-1a target genes encoding for Plasminogen activator inhibitor 1 and tumor necrosis factor alpha. Moreover, TBI-induced expression of pro-apoptotic BNIP3 was attenuated by 2ME2 treatment. Alternatively, spliced HIF-1aΔEx14 was substantially up-regulated from 6 to 48 h after TBI. In vitro, nuclear location and gene transcription activity of HIF-1aΔEx14 were impaired compared to full-length HIF-1a, but no effects on nuclear translocation of the transcriptional complex partner HIF-1b were observed. This study demonstrates that 2ME2 confers neuroprotection after TBI. While the role of alternatively spliced HIF-1aΔEx14 remains elusive, the in vivo data provide evidence that inhibition of a maladaptive HIF-1a-dependent response contributes to the neuroprotective effects of 2ME2. Keywords: 2-methoxyestradiol, alternative splicing, cerebral ischemia, HIF-1, neuroprotection, traumatic brain injury.

2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism

“…2-ME is protective against experimental autoimmune encephalomyelitis (16), neurodamage following traumatic brain injury (33), and brain infarction following middle cerebral artery occlusion-induced focal ischemia (8). These findings, along with our results, suggest that endogenous 2-ME may play an important role in mediating the protective effects of estradiol.…”

“…Indeed, 2-ME is a potential therapeutic agent that is protective against cardiovascular disease and multiple proliferative and immune disorders such as cancer and rheumatoid arthritis (12,28). Importantly, 2-ME inhibits experimental autoimmune encephalomyelitis via suppression of lymphocyte activation (16), induces neuroprotection following traumatic brain injury by inhibiting maladaptive HIF-1␣ responses (33), and reduces brain infarct size in a middle cerebral artery occlusion-induced focal ischemia rat model (8). Decreased levels of 2-ME are observed in patients with Parkinson's disease (18), and significant increases in 2-ME levels during the last months of pregnancy seem to correlate temporally with remission of clinical symptoms in some pregnant multiple sclerosis and rheumatoid arthritis patients (27,28).…”

Neuronal Nitric Oxide Synthase-Mediated Genotoxicity of 2-Methoxyestradiol in Hippocampal HT22 Cell Line

“…There are inconsistent data concerning neuroprotective and neurotoxic effects of 2-ME. Neuroprotective effects of 2-ME were reported in several mice and rat models [22,64]. 2-ME was found to suppress HIF1α and VEGF and reduce apoptosis, brain edema, and neurologic scores based on the scoring system reported by Garcia [22].…”

Gamma-Secretase Inhibitors Attenuate Neurotrauma and Neurogenic Acute Lung Injury in Rats by Rescuing the Accumulation of Hypertrophic Microglia

“…The adult rat brain showed a 52% decrease in cortical cerebral blood flow (CBF) within 15 minutes of FPI, which persisted for 4 hours and then returned to the original CBF level at 24 hours post-injury [32]. Compared to the contusion volume of the primary lesion, which was determined 15 minutes after TBI, the contusion volume in the mouse controlled cortical impact (CCI) model increased approximately two-fold over 24 hours [33]. In a rat model of FPI, the contusion volume increased approximately six-fold over 4 days compared to that in the primary lesion (as shown in the present study).…”