Angiotensin 1-7 Rescues Cognitive Decline and Neuronal Loss Following Traumatic Brain Injury in Mice

Purpose of study: Traumatic brain injury (TBI) is a leading cause of death and disability in the U.S., accounting for approximately 30% of all injury deaths and 3 million TBI-related emergency visits yearly. There is limited research in the area of mitigating the post-inflammatory effects of non-fatal traumatic brain injury. Angiotensin 1-7, an endogenous peptide that acts on the MAS receptor, has recently shown to be anti-inflammatory, anti-oxidative, and vasodilatory unlike its relative, angiotensin II. We asked the question of whether Ang 1-7 modulates neuroinflammation and improves cognitive function in mice following traumatic brain injury. Methods: A controlled cortical impactor with a retractable piston was used to model a mild traumatic brain injury (mTBI). Mice either received Ang 1-7 (1 mg/kg, n=12) or normal saline (0.9%, n=12) 2 hours post-TBI and 30 minutes prior to novel objection recognition (NOR) testing on days 1, 3, 7, 14 post-TBI with tissue harvesting for hematoxylin and eosin (H&E) staining. Results: Between-group studies showed that Ang 1-7 treated mice showed significantly higher NOR ratios compared to that of the control group. Additionally, statistically significant higher neuronal count in the ipsilateral hippocampal and cortical tissues days 1, 3, 7, and 14 post-TBI was observed in the Ang-1-7 group. Conclusion: Together, these results demonstrate that Ang 1-7 significantly improves cognitive function and rescues further cell loss against secondary intrinsic injury following extrinsic mTBI and suggest that it may be a novel therapy to the effects of mild traumatic brain injury

Inhibition of p38-MAPK signaling pathway attenuates breast cancer induced bone pain and disease progression in a murine model of cancer-induced bone pain

<p>Abstract</p> <p>Background</p> <p>Mechanisms driving cancer-induced bone pain are poorly understood. A central factor implicated to be a key player in the process of tumorigenesis, osteoclastogenesis and nociception is p38 MAPK. We determined the role of p38 MAPK in a mouse model of breast cancer induced bone pain in which mixed osteolytic and osteoblastic remodeling occurs.</p> <p>Results</p> <p>In cancer-treated mice, acute as well as chronic inhibition of p38 MAPK with SB203580 blocked flinching and guarding behaviors in a dose-dependent manner whereas no effect on thresholds to tactile stimuli was observed. Radiographic analyses of bones demonstrated that chronic inhibition of p38 MAPK reduced bone loss and incidence of spontaneous fracture in cancer-treated mice. Histological analysis of bones collected from mice treated with the p38 MAPK inhibitor showed complete absence of osteoblastic growth in the intramedullary space as well as significantly reduced tumor burden.</p> <p>Conclusions</p> <p>Blockade of non-evoked pain behaviors but not hypersensitivity suggests differences in the underlying mechanisms of specific components of the pain syndrome and a possibility to individualize aspects of pain management. While it is not known whether the role of p38 MAPK signaling can be expanded to other cancers, the data suggest a need for understanding molecular mechanisms and cellular events that initiate and maintain cancer-induced bone pain for effective management for both ongoing pain as well as breakthrough pain.</p

Haploinsufficiency of tau decreases survival of the mouse model of Niemann-Pick disease type C1 but does not alter tau phosphorylation

Niemann-Pick C1 (NPC1) mouse models show neurofibrillary tangles as do human patients. A previous study in NPC1/tau double-null mutant mice showed that tau knockout nulls and heterozygotes unexpectedly had decreased survival when compared with NPC1 single mutants (Pacheco et al., Hum Molec Genetics 18:956-965, 2009). This was done in a null model of NPC1 (Npc1-/-). We have extended these results to a hypomorphic model (Npc1nmf164) and additionally studied tau phosphorylation, which has not been previously done in a tau heterozygote. As before, NPC1/tau double-mutant mice had shortened survival when compared with the NPC1 single mutant. Tau dosage was not affected by the Npc1 mutation. The increased phosphorylation of tau-ser396 previously noted in NPC1 mouse models was also present, but unaffected by the tau knockout, indicating that changes in tau phosphorylation are not the cause of decreased survival in NPC1/tau double mutants. Thus, the reason for shortened survival of NPC1 mouse models with concomitant tau haploinsufficiency is uncertain.12 month embargo; published 13 August 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain

Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain. Keywords: Spared nerve injury, Neuropathic pain, CRMP2, Cyclin-dependent kinase 5, Phosphorylatio