Antagonism of purinergic signalling improves recovery from traumatic brain injury

Abstract

The recent public awareness of the incidence and possible long-term consequences of traumatic brain injury only heightens the need to develop effective approaches for treating this neurological disease. In this report, we identify a new therapeutic target for traumatic brain injury by studying the role of astrocytes, rather than neurons, after neurotrauma. We use in vivo multiphoton imaging and show that mechanical forces during trauma trigger intercellular calcium waves throughout the astrocytes, and these waves are mediated by purinergic signalling. Subsequent in vitro screening shows that astrocyte signalling through the 'mechanical penumbra' affects the activity of neural circuits distant from the injury epicentre, and a reduction in the intercellular calcium waves within astrocytes restores neural activity after injury. In turn, the targeting of different purinergic receptor populations leads to a reduction in hippocampal cell death in mechanically injured organotypic slice cultures. Finally, the most promising therapeutic candidate from our in vitro screen (MRS 2179, a P2Y1 receptor antagonist) also improves histological and cognitive outcomes in a preclinical model of traumatic brain injury. This work shows the potential of studying astrocyte signalling after trauma to yield new and effective therapeutic targets for treating traumatic brain injury.

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

“…In vivo imaging studies on the exposed rat cortex revealed that a micromechanical impact triggered intercellular Ca 2+ waves in cortical astrocytes which were attenuated by addition of the ATP-degrading enzyme apyrase. The data suggested that mechanical trauma to astrocytes in vivo triggers ATP-mediated Ca 2+ waves transmitting even beyond the initial epicenter of mechanical trauma [98]. These studies imply that cultured astrocytes represent a reactive phenotype different from in situ Bresting^astrocytes.…”

“…More recent studies suggest, however, that in vivo astrocytic calcium waves occur only following a pathological insult [356]. This includes brain ischemia [357] and traumatic brain injury [98]. In vivo imaging studies on the exposed rat cortex revealed that a micromechanical impact triggered intercellular Ca 2+ waves in cortical astrocytes which were attenuated by addition of the ATP-degrading enzyme apyrase.…”

Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury

“…We used the mixed model structure to evaluate the latency times over consecutive trials in the first half (trials 1-4) and second half (trials 5-8), consistent with previous work. 15 If the mixed model produced significant differences for the fixed effects measures and/or their interaction across these two trial groups, we then used the Tukey honest significant difference (HSD) testing for post hoc comparison.…”

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

“…A study investigated the role of P2 receptor antagonists in TBI [93]. A controlled cortical impact was applied to the head of mice with a pneumatic impactor.…”

“…The mechanism of protection is unclear, but reduced release of glutamate may inhibit excitotoxicity. Blocking hippocampal P2Y 1 receptors might lead to an enhancement of synaptic signaling which might trigger pro-survival pathways and antioxidant mechanism [93].…”