In vitro and in vivo effects of a novel dimeric inhibitor of PSD‐95 on excitotoxicity and functional recovery after experimental traumatic brain injury

Abstract

PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01-147 (10 mg/kg), the non-competitive NMDAR-receptor antagonist MK-801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801 provided robust neuroprotection against NMDA-induced toxicity in cultured cortical neurons, UCCB01-147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD-95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration.

Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury

“…Therefore, the interaction between glutamate receptors and postsynaptic scaffold proteins contributes to the modulation of neuronal injury after TBI. Disruption of the interaction between PSD-95 and NR2B, a NMDAR subunit, reduced brain damage and improved neurological dysfunction after TBI 4,10 . Furthermore, Homer 1a attenuated neuronal injury and brain damage after TBI by differentially regulating group I mGluRs 11 .…”

“…The postsynaptic density-95 (PSD-95) protein is another important postsynaptic scaffold protein that binds NR2B, a subunit of NMDAR, together with neuronal nitric oxide synthase (nNOS). Recently, pharmacological inhibitors that uncouple PSD-95 from NMDAR signaling have been shown to reduce trauma-induced brain damage and neurological deficits 4 . These results indicated that postsynaptic scaffold proteins are potentially valuable for investigating the mechanism underlying the pathogenesis of TBI and potential targets for TBI interference.…”

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

“…Further, a rodent model of CCI showed loss of PSD-95 with loss of neuronal NeuN in contused cortex and directly correlated with behavioral abnormalities [ 64 ]. UCCB01-147 [also known as Tat-NPEG4(IETDV)(2), (Tat-N-dimer)], a dimeric PSD-95 inhibitor, was observed to be neuroprotective in an experimental stroke model [ 65 ] but failed to demonstrate those beneficial effects in experimental TBI [ 66 ]. Therefore, it can be argued that PSD-95 alone or with other effector proteins may provide a potential clinical therapeutic target to improve memory and learning deficits but must be translated carefully for better results post-TBI.…”

Global connectivity and function of descending spinal input revealed by 3D microscopy and retrograde transduction

“…Prior studies with retrograde dyes and 2D imaging approaches have cataloged mouse supraspinal populations (Liang et al, 2012b(Liang et al, , 2011; the 3D approach now offers a means to place these populations into spatial context while accelerating the task of surveying populations globally. For example, in experimental brain syndromes such as stroke, traumatic brain injury and genetic diseases that involve descending motor pathways, this approach could clarify when and where axonal abnormalities originate, while quantifying in an unbiased way neurons that maintain intact connections (Carron et al, 2016;Sommer et al, 2017). Variable sparing of axons often complicates spinal injury experiments, and thus one application of this technique would be to immediately supply AAV2-Retro distal to injury site, followed by 3D imaging throughout the brain to rapidly quantify the distribution of virally labeled (spared) axons and neurons.…”