Authored by Esmerina Tili*
Abstract
Introduction:: The current study aimed to develop an easy approach to the different neuromuscular disorders causing hand weakness.
Methods: 81 patients suffering from unilateral or bilateral hand weakness were subjected to neurological examination and electrophysiological assessment and imaging of the cervical cord by Magnetic resonance image for patients with mixed upper and lower motor neuron lesion.
Results:Inflammatory disorders were [24]; demyelinating neuropathy (5), axonal neuropathy (17), polymyositis (1) and myasthenic myopathy (1). Compressive disorders were [22]; median entrapment (11), radial and ulnar entrapment (5), degenerative radiculopathy, myelopathy (3), cervical syringomyelia (1) and thoracic outlet syndrome (1). Motor neuron disease (17). Hereditary disorders were [12]; myotonia (7), myopathy (2) and hereditary neuropathy (3). Traumatic disorders were [6]; radial and ulnar injury (4) and brachial plexus injury (2).
Discussion:We concluded that; inflammatory disorders were the most frequent causes of hand weakness. An algorithmic approach of hand weakness was concluded.
Keywords:Hand weakness; Neurophysiology; Neuropathy; Myopathy; Myasthenia; Diagnostic approach
Abstract
Non-coding RNAs whether short (such as microRNAs) or long >200 nucleotides, are implicated in a wide array of physiological and pathological processes including spinal cord injury. In this review, we will focus specifically on long non-coding RNAs and their involvement in spinal cord injury. We will first provide a background on the cellular and molecular mechanisms involved in spinal cord injury and emphasize the need to better understand these processes for developing effective therapeutics. Next, we will review the long non-coding RNAs reported to be changed by injury to the spinal cord, the study models and the techniques used, as well as the outcomes of injury when the expression of these transcripts is modified. We will finally discuss what can be done in the future for the experimental application of long noncoding RNAs in spinal cord injury.
Introduction
Spinal cord injury (SCI) and paralysis can be the result from: (I) a non-traumatic etiology such as viral infections (e.g. poliovirus can trigger poliomyelitis causing motor neuron death [1]), arthritis, and autoimmune disorders (e.g. multiple sclerosis in which white matter demyelination results in several neurological symptoms including gait ataxia, weakness, and optic neuritis [2]); (II) a traumatic injury (for example a motor vehicle accident); or (III) an ischemic event, caused by ischemic conditions imposed on the spinal cord during surgical interventions [3]. This review will only be focused on traumatic and ischemic spinal cord damage and longnoncoding RNAs.
A-Spinal Cord Injury
In traumatic SCI, the injury is sustained from a traumatic event (e.g. car accidents, falls, violence) [4] and can result in contusion [5], vertebral fracture and dislocation [6], or transection [7]. The damage caused by the initiating traumatic event is referred to as the primary injury; secondary injury refers to the biochemical reactions that follow the primary insult and exacerbate the injury to the spinal cord [8]. Secondary injury involves ionic imbalances and glutamate excitotoxicity, inflammation and inflammatory cytokine signaling, lipid peroxidation (LP), demyelination, axonal dieback, cell death, and gliosis and fibrosis [8]. The mechanical forces imparted by the primary injury disrupts the local vasculature and damages cells thus yielding higher amounts of extracellular debris including glutamate [8]; higher concentrations of extracellular glutamate dysregulates ionic homeostasis which ultimately promotes cell death [9]. Deleterious enzymes such as nitric oxide synthase and phospholipase A, activated by glutamate excitotoxicity [9], produce free radicals which initiates LP, a process that yields toxic 4-hydroxynonenal and 2-propenal [10] and produces protein adducts [11]. Free radicals generated from nitric oxide synthase and LP protein adducts also contribute to DNA damage which can result in neuronal death [12-14]. Vascular disruption results in neutrophil extravasation which, along with microglial activation, propagates inflammatory signaling through elevated inflammatory cytokine and chemokine secretion. Reports indicate that these processes exert some regenerative/neuroprotective signals at the synapse but due to the high intensity of the immune response at this point it is rather the detrimental signals that dominate the secondary effects in the injured spinal cord [15,16]. This inflammatory milieu further exacerbates the damage caused by the primary insult via activation of cell death programs (e.g. apoptosis, necroptosis), astrogliosis, glial scar formation, and extracellular matrix remodeling [8].
Ischemic SCI (ISCI) involves an ischemic etiology such as atherosclerotic disease, aortic pathologies, aortic surgery, and aortic grafting [17]. Damage to the spinal cord in ISCI is potentiated by ischemic/reperfusion (I/R) injury, which can occur during open surgical repair of thoracoabdominal aortic aneurysms (TAAA). In open surgery of TAAA, a cross-clamp is employed across the damaged aorta while the graft is implanted. Transient use of the cross-clamp induces ischemia of the spinal cord followed by blood flow reperfusion [18]. I/R of the spinal cord exacerbates damage as free radicals are generated and hyperemia contributes to spinal cord edema which subsequently induce neuronal death and LP [19]; concurrently, an inflammatory response in ISCI also contributes to damage through inflammatory cytokine secretion [20, 21]. Studies of I/R injury in rats indicate that targeting components of the inflammatory cascade attenuated I/R injury and supported neurological improvement [22,23]. In addition, deletion of the proinflammatory microRNA miR-155 in mice reduced the incidence of paralysis after aortic cross-clamping in mice, further suggesting an inflammatory component to ISCI damage and paralysis after open aortic repair [21].
In the United States, the prevalence of SCI is reported to be 906 per million [24], and 90% of SCI cases have a traumatic etiology [4]. The impact of SCI upon patients and their families is tremendous: the damage caused by SCI can cause loss of function at and/or below the level of the neurological injury, patients who sustained the injury between the age of 25 and 34 years have a life expectancy of 38 years post-injury [25], and per individual economic burden can reach as high as $3.0 million [26]. As of 2013, the only approved pharmaceutical therapy for SCI is methylprednisolone. Methylprednisolone possesses anti-inflammatory characteristics and attenuates LP yet it demonstrates varying efficacy in patients [27]. Accordingly, it is necessary to develop novel therapeutics aimed at attenuating neurological injury, promoting functional recovery, and bolstering endogenous regenerative efforts.
B- Long noncoding RNAs
Long non-coding RNAs (Lnc-RNAs), as the name implies, are RNA transcripts longer than 200 nucleotides that are for the most part not translated [28]. While there are also some Lnc-RNAs that have been shown to encode very short peptides [29], the research in this field is scarce [30]. Lnc-RNAs can be generated from the transcription of intergenic sequences (large intergenic noncoding RNA ie. Linc-RNA), from the antisense strand of recognized transcription units, from transcribed pseudogenes, from spliced-out introns, or from extraneous transcripts produced at transcription start sites [28]. Lnc-RNAs exert biologically relevant functions through a variety of mechanisms including as a scaffold for epigenetic regulators and as molecular sponges through RNARNA interactions [28]. The biological functions of Lnc-RNAs involve modulation of gene expression during development, the pathogenesis of cancer, and senescence [28,30]. The rest of this review will center on examining the role and potential therapeutic applicability of Lnc-RNAs in SCI.
Lnc-RNAs in SCI
As noted earlier, one mechanism by which Lnc-RNAs can exert their effects is through serving as a decoy for regulatory factors (sponging). Binding of a particular Lnc-RNA to a microRNA through complementary base recognition impairs the microRNA from binding to its targets; thus, the micrRNA is unable to reduce the expression of its protein-coding target transcripts, ultimately changing cellular homeostatic conditions. Lnc-RNA-microRNA interactions are the most extensively studied due to the possibility of predicting (in silico) Lnc-RNA-microRNA pairs.
In a contusion model of rat SCI, Lnc-RNA MALAT1, which was studied based on its roles in other diseases such as non-small cell lung carcinoma, was suggested to propagate inflammatory processes by interacting with miR-199b [31], a known regulator of the NF-kB inflammation pathway [32]. In fact, the study indicated that in vitro Lnc-RNA MALAT1 knockdown (KD) reduced tumor necrosis factor-alpha (TNF-α) and interleukin 1 Beta (IL-1β); these effects were reversed for the Lnc-RNA MALAT1 KD + miR-199b inhibition condition. Furthermore, Lnc-RNA MALAT1 (increased in SCI rats) is inversely correlated with miR-199b (decreased in SCI rats) expression and in vivo Lnc-RNA MALAT1 inhibition with lentiviral (LV)-siRNA-MALAT1 reduced inflammatory cytokine production and improved motor scores; these effects were reversed with antago-miR-199b treatment [31]. On the other hand, Qiao et al. proposed that Lnc-RNA MALAT1 has a beneficial effect after I/R SCI in rats by noting that Lnc-RNA MALAT1 overexpression in oxygen-glucose deprived neurocytes reduced miR-204, increased anti-apoptotic Bcl-2 and overall reduced apoptosis. These results translated to in vivo studies and I/R rats subjected to Lnc-RNA MALAT1 overexpression exhibited lower motor deficit indices while miR-204 overexpression reversed the anti-apoptotic effects of Lnc- RNA MALAT1 overexpression [33]. We speculate that the contrasting effects of Lnc-RNA MALAT1 in these two studies could be due to the utilization of different SCI models, and the fact that Zhang et al. studied Lnc-RNA MALAT1 in microglial cell culture while the study conducted by Qiao et al. examined expression in neurocytes. These differential results raise a key point: it is important to acknowledge the cellular components involved in SCI and the cellular origin of genes/proteins, Lnc-RNAs, or microRNAs that are changed after SCI. In addition, considering the fact that microRNAs target different transcripts at different concentrations [34,35], depending on the level of expression of microRNAs and their interacting sponging Lnc-RNA, differential functional outcomes are expected. Another Lnc-RNA transcript involved in SCI is XIST. Studies have indicated that Lnc-RNA XIST has pro-apoptotic and pro-inflammatory role in SCI. Specifically, Zhao et al. indicates that in in vitro and in vivo models of SCI, Lnc-RNA XIST is upregulated and exerts deleterious effects through targeting the miR-27a/Smurf1 axis which was confirmed with a dual-luciferase assay and anti-miR-27a treatment in microglial cell culture; furthermore, in a contusion SCI rat model, Lnc-RNA XIST silencing using LV-sh-XIST infection decreased TNF-α and IL-6 secretion, and Bax and cleaved-Caspase-3 expression, two genes involved in apoptosis [36]. Gu et al. suggested that Lnc-RNA XIST may sponge miR-494, an oncomiR in hepatocellular carcinoma, which was confirmed using a luciferase assay; LV-sh-Lnc-RNA XIST administration in a contusion SCI rat model increased miR- 494 expression, activated the PI3K/Akt pathway, and improved functional recovery post-injury. The beneficial effects of LV-sh-Lnc- RNA XIST administration were reversed when antago-miR-494 was also administered supporting the interaction between Lnc-RNA XIST and miR-494 [37]. It is interesting that this study found that reduction of expression of a Lnc-RNA using shRNA against XIST caused increased expression of its target microRNA. Our current understanding is that Lnc-RNAs bind and block the activity of a microRNA without necessarily changing the level of expression of this microRNA. Blocking the function of a microRNA does not necessary translate to decreased expression. Therefore, we caution that much more work should be done to better characterize and understand the outcomes of Lnc-RNA-microRNA interactions.
To read more about this article...Open access Journal of Archives in Neurology & Neuroscience
Please follow the URL to access more information about this article
To know more about our Journals....Iris Publishers
To know about Open Access Publishers
No comments:
Post a Comment