Traumatic brain injury (TBI) causes neuronal cell death, combined with astroglial proliferation and inflammation associated with the activation of microglia, which contributes to irreversible tissue damage. Such secondary injury begins within seconds to minutes after the insult and may continue for days, weeks and potentially even months to years. Recent evidence from our laboratory shows chronic inflammation in the CNS lasting at least 6 months after injury. Inflammation may contribute to chronic neurodegeneration after trauma as well as to disorders such as Alzheimer's disease (AD) or Parkinson's syndrome. Pilot studies in our laboratory have indicated that inflammation may be inhibited by activation of mGluR5 receptors in microglia. Furthermore, our data suggest that mGluR5 effects may be mediated by actions on the NADPH oxidase enzyme, which functions to produce reactive oxygen species (ROS) by microglia and may play a significant role in persistent activation of microglia following injury. The proposed studies are intended to address the following hypotheses: (1) NADPH oxidase inhibition reduces microglial activation, production of pro-inflammatory factors and associated neurological dysfunction after TBI;(2) mGluR5 stimulation attenuates microglia activation and secondary neuronal cell death, and improves functional outcomes after TBI;(3) mGluR5, but not mGluR1, modulates microglial activation and neurotoxicity in primary microglia cultures, a microglial cell line, and microglia/neuronal co-cultures, in part through inhibition of NADPH oxidase;and (4) the G1q-protein signal transduction pathway is the critical component of the mGluR5 signal transduction events leading to inhibition of microglial NADPH oxidase and suppression of microglial activation.
Specific aims are to demonstrate: (1) the importance of NADPH oxidase in microglial activation and correlated production of pro-inflammatory factors in the chronic neuronal cell loss and associated neurological dysfunction after TBI;(2) that mGluR5 stimulation attenuates microglial activation, decreases neuronal cell death and improves functional outcomes after TBI in contrast to mGluR5 global knockout animals that show greater microglial activation and neuronal cell death. We will also distinguish the relative roles of microglial versus neuronal mGluR5 using conditional/inducible knockout mice;(3) that mGluR5, but not mGluR1, modulates microglial activation and neurotoxicity in multiple cell culture models of microglial stimulation;and (4) that the G1q-protein signal transduction pathway is initiated by mGluR5 stimulation and is critical for attenuation of microglial activity by preventing activation of the NADPH oxidase enzyme complex, using in vitro microglial cell models.

Public Health Relevance

There are 1 million incidences of traumatic brain injury (TBI) per year nationally. Patients with TBI demonstrate evidence of prolonged microglial activation that lasts at least 3 weeks post-injury. The proposed work, in which we will investigate the neuroprotective effects of microglial and neuronal mGluR5, will provide initial investigation to a novel therapeutic approach for TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037313-13
Application #
8213620
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Hicks, Ramona R
Project Start
1999-02-03
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
13
Fiscal Year
2012
Total Cost
$422,028
Indirect Cost
$140,676
Name
University of Maryland Baltimore
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Faden, Alan I; Loane, David J (2015) Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Neurotherapeutics 12:143-50
Loane, David J; Stoica, Bogdan A; Tchantchou, Flaubert et al. (2014) Novel mGluR5 positive allosteric modulator improves functional recovery, attenuates neurodegeneration, and alters microglial polarization after experimental traumatic brain injury. Neurotherapeutics 11:857-69
Loane, David J; Kumar, Alok; Stoica, Bogdan A et al. (2014) Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol 73:14-29
Loane, David J; Stoica, Bogdan A; Byrnes, Kimberly R et al. (2013) Activation of mGluR5 and inhibition of NADPH oxidase improves functional recovery after traumatic brain injury. J Neurotrauma 30:403-12
Byrnes, Kimberly R; Loane, David J; Stoica, Bogdan A et al. (2012) Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury. J Neuroinflammation 9:43
Byrnes, Kimberly R; Fricke, Stanley T; Faden, Alan I (2010) Neuropathological differences between rats and mice after spinal cord injury. J Magn Reson Imaging 32:836-46
Loane, David J; Faden, Alan I (2010) Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci 31:596-604
Byrnes, Kimberly R; Stoica, Bogdan; Loane, David J et al. (2009) Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity. Glia 57:550-60
Loane, David J; Stoica, Bogdan A; Pajoohesh-Ganji, Ahdeah et al. (2009) Activation of metabotropic glutamate receptor 5 modulates microglial reactivity and neurotoxicity by inhibiting NADPH oxidase. J Biol Chem 284:15629-39
Byrnes, Kimberly R; Stoica, Bogdan; Riccio, Angela et al. (2009) Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents. Ann Neurol 66:63-74

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