Combined scopolamine and morphine treatment of traumatic brain injury in the rat

doi:10.1016/0006-8993(93)90614-S

Brain Research

Volume 617, Issue 1, 16 July 1993, Pages 69-75

https://doi.org/10.1016/0006-8993(93)90614-S Get rights and content

Abstract

Previous studies have indicated that either scopolamine (1.0 mg/kg) or morphine (10.0 mg/kg) administered to rats prior to or soon after moderate fluid percussion traumatic brain injury (TBI) reduces behavioral deficits associated with injury. In this study, a series of experiments examined the effects of a combination of these drugs, as well as each drug individually, on behavioral outcome, brain temperature, and systemic physiological responses to TBI. Experiment I: a single systemic bolus injection of scopolamine (n = 10), morphine (n = 11), scopolamine plus morphine (n = 11), or saline (n = 10) was administered to rats 15 min prior to TBI. Animals were assessed on beam-walking behavioral performance for 5 days after injury. Scopolamine alone or morphine alone significantly reduced (P < 0.05) deficits produced by injury. Treatment with a combination of scopolamine and morphine provided greater protection on beam-walking behavioral measures than either drug alone. Experiment II: morphine raised brain temperature on uninjured rats (n = 5) to a mean of39.3°C±0.3by60min post-injection. Neither scopolamine (n = 5) nor scopolamine plus morphine (n = 5) altered brain temperature. Experiment III: scopolamine (n = 7) significantly raised heart rate for 5 min after injury. Saline (n = 8), morphine (n = 9) and scopolamine plus morphine (n = 7) significantly lowered heart rate after injury. All four groups had similar hypertensive responses to TBI which peaked at 10 s after injury. The results confirm that pharmacological blockade of muscarinic receptors or stimulation of μ opioid receptors reduces functional deficits associated with TBI. The greater protection observed with the combined drug treatment indicates that a cocktail of pharmacological treatments has the potential for providing greater benefit than single drug strategies.

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Also, pretreatment with 10.0 mg/kg of morphine significantly reduced neurological deficits associated with injury (Hayes et al., 1990). In a similar study, pretreatment with morphine (10 mg/kg) significantly improved beam-walk latency compared to the vehicle group (Lyeth et al., 1993). Lesnik et al. evaluated the opioid system involvement in cognitive deficit in mild TBI.
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CNS injuries, such as traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and cerebral ischemic stroke, are important causes of death and long-term disability worldwide. As an important class of pervasive genes involved in many pathophysiological processes, long non-coding RNAs (lncRNAs) have received attention in the past decades. Multiple studies indicate that lncRNAs are abundant in the CNS and have a key role in brain function as well as many neurological disorders, especially in CNS injuries. Several investigations have deciphered that regulation of lncRNAs exert pro-angiogenesis, anti-apoptosis, and anti-inflammation effects in CNS injury via different molecules and pathways, including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch, and p53. Thus, lncRNAs show great promise as molecular targets in CNS injuries. In this article, we provide an updated review of the current state of our knowledge about the relationship between lncRNAs and CNS injuries, highlighting the specific roles of lncRNAs in CNS injuries.
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Cholinergic stimulation results in seizure activity and significant neuronal damage in the hippocampus (Olney et al., 1983; Turski et al., 1983) suggesting that a TBI-induced cholinergic activation could have similar effects that might be relevant to post-traumatic epilepsy progression. Blockade of the muscarinic acetylcholine receptor (mAChR) acutely after moderate TBI showed neuroprotective effects enhancing the behavioral recovery after injury (Lyeth et al., 1993). Early suppression of muscarinic receptor activity and cessation of abnormally-elevated acetylcholine levels might prevent a TBI- and cholinergic-mediated acceleration of epileptogenic processes.
Post-traumatic epilepsy (PTE) is diagnosed in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments.
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The central nervous system (CNS) plays a pivotal role in virtually all mammalian functions, including cognitive behavior, motility, perception, and homeostasis/regulation. Trauma to the CNS can therefore have devastating consequences due to the disruption of complex neural circuitry underlying these critical functions, which is compounded by the limited regenerative capacity of the brain and spinal cord. Rat models of both spinal cord injury and traumatic brain injury are described in this chapter. Induction of specific models and selected outcome measures are reviewed. Benefits of using rat models, potential confounding factors on animal experiments, and complications for interpretation of data obtained from these experiments are highlighted.
Neuroprotection by anaesthetics in rodent models of traumatic brain injury: a systematic review and network meta-analysis
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Anaesthetic neuroprotection in the setting of traumatic brain injury (TBI) remains unproved and is based upon the results in preclinical experiments. Here, we sought to synthesise the results in rodent models of TBI, and to evaluate the effects of publication bias, experimental manipulation, and poor study quality on the effect estimates.
After a systematic review, we used pairwise meta-analysis to estimate the effect of anaesthetics, opioids, and sedative–hypnotics on neurological outcome, and network meta-analysis to compare their relative efficacy. We sought evidence of bias related to selective publication, experimental manipulation, and study quality.
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Anaesthetics do provide neuroprotection in rodent models of TBI. The effect-size estimates do not appear to be exaggerated by selective publication, experimental manipulation, or study design. The main shortcoming of the included studies were small sample sizes leading to low power and imprecision, which precluded the network meta-analysis from providing a meaningful ranking for efficacy amongst the drugs. Reliable preclinical investigations of neuroprotection by anaesthetics will require larger sample sizes.
Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?
2016, Progress in Neurobiology
Citation Excerpt :
Specifically, polytherapies have either been neutral, meaning they failed to alter outcome (Faden, 1993; Smith et al., 1993; Yan et al., 2000; Çelik et al., 2006; Todd et al., 2006; Kline et al., 2007b; Oztürk et al., 2008), or have been negative, which is defined as worsening endpoint measures or suppressing the beneficial effects of treatments that on their own were effective (Faden, 1993; Guluma et al., 1999; Kline et al., 2002; Griesbach et al., 2008). Fortunately, a small number of early studies revealed positive benefits (Lyeth et al., 1993; Yan et al., 2000; Menkü et al., 2003; Barbre and Hoane, 2006; Mahmood et al., 2007), suggesting that the correct combination of treatments during the appropriate therapeutic window can be efficacious and thus served as the impetus for further investigation into this complex, but more realistic and potentially more successful strategy for rehabilitation of TBI. While combined treatment approaches are also utilized in other central nervous system disorders, such as stroke (Gisvold et al., 1984; Liu et al., 2010; Wang et al., 2012; Ji et al., 2015; Schuch et al., 2016) and spinal cord injury (Koopmans et al., 2009; Tanabe et al., 2009; Lee et al., 2012; Wilems et al., 2015), the aim of this review is to highlight the current state of combinational treatment approaches for neurobehavioral and cognitive recovery in experimental TBI.
Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.

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Combined scopolamine and morphine treatment of traumatic brain injury in the rat

Abstract

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Neuropeptides

A microiontophoretic study of the actions of mu-, delta-, and kappa-opiate receptor agonists in the rat brain

Br. J. Pharmacol.

Marked protection by moderate hypothermia after experimental traumatic brain injury

J. Cereb. Blood Flow Metab.

A fluid percussion model of experimental brain injury in the rat

J. Neurosurg.

The role of excitatory amino acid receptors and NMDA receptors in traumatic brain injury

Science

Analysis of acetylcholine release following concussive brain injury in the rat

J. Neurotrauma

Effect of naloxone on systemic and cerebral responses to experimental concussive brain injury in cats

J. Neurosurg.

Pretreatment with phencyclidine, anN-methyl-d-aspartate receptor antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury

J. Neurotrauma