A Multi-Model Pipeline for Translational Intracerebral Haemorrhage Research

Abstract

Apart from acute and chronic blood pressure lowering, we have no specific medications to prevent intracerebral haemorrhage (ICH) or improve outcomes once bleeding has occurred. One reason for this may be related to particular limitations associated with the current pre-clinical models of ICH, leading to a failure to translate into the clinic. It would seem that a breakdown in the ‘drug development pipeline’ currently exists for translational ICH research which needs to be urgently addressed. Here, we review the most commonly used pre-clinical models of ICH and discuss their advantages and disadvantages in the context of translational studies. We propose that to increase our chances of successfully identifying new therapeutics for ICH, a bi-directional, 2- or 3-pronged approach using more than one model species/system could be useful for confirming key pre-clinical observations. Furthermore, we highlight that post-mortem/ex-vivo ICH patient material is a precious and underused resource which could play an essential role in the verification of experimental results prior to consideration for further clinical investigation. Embracing multidisciplinary collaboration between pre-clinical and clinical ICH research groups will be essential to ensure the success of this type of approach in the future.

Revisiting promising preclinical intracerebral hemorrhage studies to highlight repurposable drugs for translation

“…The current pipeline for preclinical investigation using in vivo models is not working for translation to the clinic for ICH patients 15 . Previous experience with ischemic stroke research and the failure to translate from preclinical trials has resulted in a lack of confidence in the progression to the clinic for ICH.…”

“…Progressing drugs into the clinic requires multidisciplinary research, including the use of clinically relevant material such as patient blood, aspirated hematoma tissue, and postmortem brains for experimental target validation ( Figure 1 ). 15 Further emphasis on accurate translational preclinical strategies such as drug delivery methods and timing 16 and confirmation in spontaneous ICH models is also required. There has been a historical trend for translational failure in stroke research, 17 and as such there has been a general lack of enthusiasm in recent years from the pharmaceutical industry to support the development of novel compounds for stroke.…”

Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice

“…We induced the ICH model as previously described [ 14 , 15 ]. Briefly, the mice were intraperitoneally injected with ketamine/xylazine (100/10 mg/kg), and were placed prone in a stereotactic head frame (Kopf Instruments, Tujunga, CA) after being deeply anesthetized.…”

Letter to “AAV/BBB-Mediated Gene Transfer of CHIP Attenuates Brain Injury Following Experimental Intracerebral Hemorrhage”

“…The collagenase could induce potential neuroinflammatory reactions in ICH modeling. As the TNF-α is a key activator of necroptosis, potential neuroinflammatory properties induced by collagenase may affect the actual extent of necroptosis [2,3]. How to evaluate the side effects of collagenase on inflammatory response and necroptosis in this study?…”