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Intrastriatal Injection of Autologous Blood or Clostridial Collagenase as Murine Models of Intracerebral Hemorrhage
Published on: July 3, 2014
Inhibition of Src family kinases improves cognitive function after intraventricular hemorrhage or intraventricular
Da Zhi Liu1, Ben Waldau2, Bradley P Ander1
11 Department of Neurology and the M.I.N.D. Institute, University of California at Davis, Sacramento, USA.
Insights
Intraventricular hemorrhage causes memory loss by damaging hippocampal neurons. Inhibiting Src family kinases, particularly Fyn, protects against this neuronal damage and memory deficits.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Intraventricular hemorrhage (IVH) is a known cause of spatial memory loss.
- The precise mechanisms underlying IVH-induced memory deficits remain unclear.
- Previous research linked traumatic brain injury-induced memory loss to Src family kinase activation.
Purpose of the Study:
- To investigate whether blood in the ventricles activates Src family kinases, leading to spatial memory loss.
- To determine if thrombin, a component of blood, is sufficient to cause hippocampal neuron death and memory deficits.
- To evaluate the therapeutic potential of inhibiting Src family kinases in mitigating IVH-induced brain damage and memory impairment.
Main Methods:
- Modeled non-traumatic IVH in adult rats by infusing whole blood or thrombin into the lateral ventricles.
- Assessed hippocampal neuron survival at various time points post-infusion (1 day to 5 weeks).
- Evaluated spatial memory function using the Morris water maze (29–33 days post-infusion).
- Administered Src family kinase inhibitors (PP2 systemically, siRNA-Fyn intraventricularly) to assess their protective effects.
Main Results:
- Intraventricular infusion of blood or thrombin led to significant hippocampal neuron loss and spatial memory deficits 5 weeks later.
- Intraventricular thrombin alone was sufficient to induce hippocampal neuron death and spatial memory loss.
- Systemic administration of the Src family kinase inhibitor PP2 or intraventricular injection of siRNA-Fyn prevented neuronal loss and memory deficits.
Conclusions:
- Thrombin mediates hippocampal neuron death and spatial memory deficits following intraventricular hemorrhage.
- Inhibition of Src family kinases, including Fyn, effectively blocks the neurotoxic effects and memory impairments caused by IVH.
- Targeting Src family kinases represents a potential therapeutic strategy for managing cognitive deficits associated with intraventricular hemorrhage.
Abstract:
Intraventricular hemorrhage causes spatial memory loss, but the mechanism remains unknown. Our recent studies demonstrated that traumatic brain injury activates Src family kinases, which cause spatial memory loss. To test whether the spatial memory loss was due to blood in the ventricles, which activated Src family kinases, we infused autologous whole blood or thrombin into the lateral ventricles of adult rats to model non-traumatic intraventricular hemorrhage. Hippocampal neuron loss was examined 1 day to 5 weeks later. Spatial memory function was assessed 29 to 33 days later using the Morris water maze. Five weeks after the ventricular injections of blood or thrombin, there was death of most hippocampal neurons and significant memory deficits compared with sham operated controls. These data show that intraventricular thrombin is sufficient to kill hippocampal neurons and produce spatial memory loss. In addition, systemic administration of the non-specific Src family kinase inhibitor PP2 or intraventricular injection of siRNA-Fyn, a Src family kinase family member, prevented hippocampal neuronal loss and spatial memory deficits following intraventricular hemorrhage. The data support the conclusions that thrombin mediates the hippocampal neuronal cell death and spatial memory deficits produced by intraventricular blood and that these can be blocked by non-specific inhibition of Src family kinases or by inhibiting Fyn.
