Acute treatment with the 5-HT1A receptor agonist 8-OH-DPAT and chronic environmental enrichment confer neurobehavioral benefit after experimental brain trauma

Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Behavioural Brain Research (Impact Factor: 3.03). 03/2007; 177(2):186-94. DOI: 10.1016/j.bbr.2006.11.036
Source: PubMed


Acute treatment with the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or chronic environmental enrichment (EE) hasten behavioral recovery after experimental traumatic brain injury (TBI). The aim of this study was to determine if combining these interventions would confer additional benefit. Anesthetized adult male rats received either a cortical impact or sham injury followed 15min later by a single intraperitoneal injection of 8-OH-DPAT (0.5mg/kg) or saline vehicle (1.0mL/kg) and then randomly assigned to either enriched or standard (STD) housing. Behavioral assessments were conducted utilizing established motor and cognitive tests on post-injury days 1-5 and 14-18, respectively. Hippocampal CA(1)/CA(3) neurons were quantified at 3 weeks. Both 8-OH-DPAT and EE attenuated CA(3) cell loss. 8-OH-DPAT enhanced spatial learning in a Morris water maze (MWM) as revealed by differences between the TBI+8-OH-DPAT+STD and TBI+VEHICLE+STD groups (P=0.0014). EE improved motor function as demonstrated by reduced time to traverse an elevated narrow beam in both the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups versus the TBI+VEHICLE+STD group (P=0.0007 and 0.0016, respectively). EE also facilitated MWM learning as evidenced by both the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups locating the escape platform quicker than the TBI+VEHICLE+STD group (P's<0.0001). MWM differences were also observed between the TBI+8-OH-DPAT+EE and TBI+8-OH-DPAT+STD groups (P=0.0004) suggesting that EE enhanced the effect of 8-OH-DPAT. However, there was no difference between the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups. These data replicate previous results from our laboratory showing that both a single systemic administration of 8-OH-DPAT and EE improve recovery after TBI and extend those findings by elucidating that the combination of treatments in this particular paradigm did not confer additional benefit. One explanation for the lack of an additive effect is that EE is a very effective treatment and thus there is very little room for 8-OH-DPAT to confer additional statistically significant improvement.

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Available from: Anthony E. Kline, Jan 06, 2015
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    • "Cortical and subcortical lesions in regions such as the hippocampus occur most frequently following TBI in the frontal lobe (McDowell et al., 1997), leading to lasting working memory deficits (Fox et al., 1998), prominent anxiety (Jorge et al., 2004), and executive dysfunction (Eslinger, 1996). The neurological and behavioral effects of EE reduce TBI-induced deficits and improve recovery time (Will et al., 1977, 2004; Passineau et al., 2001; Chen et al., 2005; Gaulke et al., 2005; Giza et al., 2005; Wagner et al., 2005; Kline et al., 2007). Importantly, the cognitive benefits of EE are also demonstrated by a reduced deficit in memory performance following brain injury (Hamm et al., 1996; Will et al., 2004; Komitova et al., 2005). "
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    ABSTRACT: Environmental enrichment (EE) increases cortical weight, neuronal density, dendritic branching, and angiogenesis, all of which may be critical for functional recovery following insult. Our study was designed to determine possible benefits of pre-exposure to EE in preventing functional deficits following traumatic brain injury (TBI) to the prefrontal cortex. To examine the benefit of EE, adult male rats were placed in an enriched environment for 15 days. Enrichment was provided through social interaction, exercise, olfactory stimulation, and new objects/toys to explore. Following enrichment, experimental and age-matched controls were subjected to a moderate medial prefrontal cortex injury via controlled cortical impact (CCI). After 1 week recovery, animals were behaviorally tested to assess memory, anxiety, and sensory neglect. Lesion-induced deficits in spatial memory [Morris water maze (MWM)] were significantly attenuated in EE pre-exposed rats 18-21 days following injury. In addition, TBI-induced sensory neglect was significantly reduced in EE rats relative to non-enriched animals. No differences in anxiety-like behavior on the elevated plus maze (EPM) were detected. The behavioral data suggest that EE is neuroprotective when applied prior to TBI, resulting in improved recovery following injury.
    Frontiers in Behavioral Neuroscience 05/2013; 7:44. DOI:10.3389/fnbeh.2013.00044 · 3.27 Impact Factor
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    • "This process did not cause rupture or significant bleeding. CCI injury was produced as previously described in the extensive literature [50-55]. A cortical contusion was produced on the exposed cortex using either a controlled impactor device described by Bilgen [56] and previously used in a rat model of SCI [5,57], or a TBI-0310 TBI Model system (Precision Systems and Instrumentation, LLC, Fairfax Station, VA) as described in our TBI study [2]. "
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    ABSTRACT: Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury in the neurovascular unit following TBI. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. Peroxynitrite has been implicated in blood brain barrier (BBB) leakage, altered metabolic function, and neurobehavioral impairment. S-nitrosoglutathione (GSNO), a nitrosylation-based signaling molecule, was reported not only to reduce brain levels of peroxynitrite and oxidative metabolites but also to improve neurological function in TBI, stroke, and spinal cord injury. Therefore, we investigated whether GSNO promotes the neurorepair process by reducing the levels of peroxynitrite and the degree of oxidative injury. TBI was induced by controlled cortical impact (CCI) in adult male rats. GSNO or 3-Morpholino-sydnonimine (SIN-1) (50 μg/kg body weight) was administered orally two hours following CCI. The same dose was repeated daily until endpoints. GSNO-treated (GSNO group) or SIN-1-treated (SIN-1 group) injured animals were compared with vehicle-treated injured animals (TBI group) and vehicle-treated sham-operated animals (Sham group) in terms of peroxynitrite, NO, glutathione (GSH), lipid peroxidation, blood brain barrier (BBB) leakage, edema, inflammation, tissue structure, axon/myelin integrity, and neurotrophic factors. SIN-1 treatment of TBI increased whereas GSNO treatment decreased peroxynitrite, lipid peroxides/aldehydes, BBB leakage, inflammation and edema in a short-term treatment (4-48 hours). GSNO also reduced brain infarctions and enhanced the levels of NO and GSH. In a long-term treatment (14 days), GSNO protected axonal integrity, maintained myelin levels, promoted synaptic plasticity, and enhanced the expression of neurotrophic factors. Our findings indicate the participation of peroxynitrite in the pathobiology of TBI. GSNO treatment of TBI not only reduces peroxynitrite but also protects the integrity of the neurovascular unit, indicating that GSNO blunts the deleterious effects of peroxynitrite. A long-term treatment of TBI with the same low dose of GSNO promotes synaptic plasticity and enhances the expression of neurotrophic factors. These results support that GSNO reduces the levels of oxidative metabolites, protects the neurovascular unit, and promotes neurorepair mechanisms in TBI.
    Journal of Neuroinflammation 07/2011; 8(1):78. DOI:10.1186/1742-2094-8-78 · 5.41 Impact Factor
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    • "The positive effects of EEN have been described in young intact animals (Tees et al., 1990) after various forms of brain lesions (Einon et al., 1980; Whishaw et al., 1984) like TBI, spinal cord injury (Berrocal et al., 2007; Fischer and Peduzzi, 2007; Kline et al., 2007; Hoffman et al., 2008), and ischemia (Johansson and Ohlsson, 1996; Dahlqvist et al., 2004; Buchhold et al., 2007; Briones et al., 2009). Kempermann et al. (1997) "
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    ABSTRACT: De novo hippocampal neurogenesis contributes to functional recovery following traumatic brain injury (TBI). Enriched environment (EEN) can improve the outcome of TBI by positively affecting neurogenesis. Blast induced traumatic brain injury (bTBI) characterized by memory impairment and increased anxiety levels, is a leading cause of chronic disability among soldiers. Using a rodent model of bTBI we asked: (a) whether long-term exposure to EEN after injury can ameliorate behavioral abnormalities and (b) what the effects of EEN are at the molecular and cellular levels and on de novo neurogenesis. We found that housing injured animals in EEN resulted in significantly improved spatial memory while animals in normal housing (NH) showed persistent memory impairment. VEGF and Tau protein but not Interleukin-6 (IL-6) levels were normalized in the dorsal hippocampus (DHC) of EEN rats while all three markers remained elevated in NH rats. Interestingly, after peaking at 6 weeks post-injury, anxiety returned to normal levels at 2 months independent of housing conditions. Housing animals in EEN had no significant effect on VEGF and Tau protein levels in the ventral hippocampus (VHC) and the amygdala (AD). We also found that EEN reduced IL-6 and IFNγ levels in the VHC; these markers remained elevated following NH. We observed an increase in GFAP and DCX immunoreactivities in the VHC of NH animals at 2 months post-injury. Conversely, injured animals housed in EEN showed no increase in GFAP or DCX immunoreactivity in their VHC. In summary, long-term exposure of injured animals to EEN appears to play a positive role in the restoration of memory functions but not on anxiety, which returned to normal levels after a significant period of time. Cellular and molecular changes in response to EEN appear to be a part of neurogenesis-independent as well as dependent recovery processes triggered by bTBI.
    Frontiers in Neuroscience 04/2011; 5:42. DOI:10.3389/fnins.2011.00042 · 3.66 Impact Factor
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