lithium-chloride and Cerebral-Hemorrhage

Intracerebral hemorrhage (ICH), a subtype of stroke with high morbidity and mortality, occurs mainly in the basal ganglia and causes white matter injury (WMI), resulting in severe motor dysfunction and poor prognosis in patients. The preservation of the white matter around the hematoma is crucial for motor function recovery, but there is currently no effective treatment for WMI following ICH. Lithium has been widely used for the treatment of bipolar disorder for decades. Although the protective effects of lithium on neurodegenerative diseases and cerebral trauma have been studied in recent years, whether it can be used to alleviate WMI after ICH remains to be researched. The results of this study revealed that ICH caused significant functional and pathological abnormalities in mice. After LiCl was administered to mice with ICH, behavioural performance and electrophysiological functions were improved and ICH-induced white matter pathological injury, including myelin sheath and axonal degeneration, was ameliorated. Furthermore, LiCl treatment decreased the death of mature oligodendrocytes (OLGs) in ICH mice, which may have been attributed to the enhanced expression of brain-derived neurotrophic factor (BDNF) regulated by the LiCl-induced inhibition of glycogen synthase kinase-3β (GSK-3β). The decreased death of OLGs was closely associated with decreased destruction of the myelin sheath and alleviated degradation of the axons. In summary, this study suggests that the protective effect of lithium on WMI after ICH might be related to an increased level of BDNF and that LiCl treatment may be a potential therapeutic method to palliate WMI after ICH.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cerebral Hemorrhage; Evoked Potentials, Motor; Glycogen Synthase Kinase 3 beta; Lithium Chloride; Male; Mice; Mice, Inbred C57BL; Neural Conduction; Oligodendroglia; Signal Transduction; White Matter

Some neuroprotective agents have been used clinically to address the resulting various adverse effects after intracerebral hemorrhage (ICH). Particularly, effectively removing the hematoma is of practical significance to exert neuroprotective effects following ICH. However, such agents are still in need of development. Lithium chloride (LiCl) has shown neuroprotective effects through glycogen synthase kinase-3β (GSK-3β) inhibition in a variety of central nervous system diseases. However, the impact of LiCl on hematoma clearance and the potential molecular mechanisms have not been reported. We hypothesize that LiCl may exert neuroprotective roles after ICH, partly through promoting hematoma resolution. In this study, male Sprague-Dawley rats were subjected to ICH followed by intraperitoneal injection of LiCl (60 mg/kg). The hematoma volumes of ipsilateral hemisphere were determined using Drabkin's method. The sensorimotor deficits were evaluated by neurobehavioral tests. The expressions of target molecules involved in the process of hematoma clearance were assayed using immunofluorescence and Western blot. Our results showed that animals treated with LiCl presented significantly reduced hematoma volume after ICH, which was coupled with enhanced microglia phagocytosis and its differentiation into M2-phenotype within the first 7 days and up-regulated angiogenesis and neurogenesis in the next 7 days. Meanwhile, GSK-3β was inhibited by LiCl and β-catenin became stabilized, which was followed by up-regulation of nuclear factor erythroid 2-related factor 2 and CD36 from days 3 to 7, and increase of vascular endothelial growth factor and brain-derived neurotrophic factor from days 7 to 14. These data suggest that LiCl promotes hematoma resolution via enhancing microglia phagocytosis and M2-phenotype differentiation in the early stage (< 7 days) and angiogenesis and neurogenesis in the chronic phase (days 7-14), thus eventually improving the functional outcomes of ICH rats.

Topics: Animals; beta Catenin; Cell Differentiation; Cerebral Hemorrhage; Glycogen Synthase Kinase 3 beta; Hematoma; Lithium Chloride; Male; Microglia; Neurogenesis; Neuroprotection; Neuroprotective Agents; Phagocytosis; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

To the clinical cognitive impairment following intracerebral hemorrhage, comprehensive neuropsychological assessments and efficacious interventions have rarely been conducted. Lithium chloride, a classical treatment for bipolar disorder, has shown neuroprotective effects through glycogen synthase kinase-3β inhibition in a variety of central nervous system diseases, including stroke. Since neurons that contain glutamate play crucial roles in psychological functions, such as learning and memory, the glutamate-mediated excitotoxicity and consequent neuronal death and cognitive impairment in hippocampus may co-determine the clinical course of intracerebral hemorrhage. However, the potential molecular mechanisms have rarely been demonstrated in intracerebral hemorrhage researches. In this study, Male Sprague-Dawley rats, subjected to intrastriatal blood infusion, were treated with lithium chloride and underwent neurobehavioral test for equivalent injury severity and neurological functional deficits, Morris water maze test for cognitive impairment, high performance liquid chromatography analysis for excitotoxic index determination, immunohistochemistry analysis for neuronal apoptosis, and Western blot analysis for glycogen synthase kinase-3β activity. Our results showed lithium chloride inhibited glycogen synthase kinase-3β activation, which on one hand, suppressed downstream CRMP-2/NR2B, thus diminishing the excitotoxic index level; and on the other, stabilized β-catenin, thus modulating its downstream apoptosis-related factors such as NF-κB, Bcl-2 and Bax. Meanwhile, glycogen synthase kinase-3β inactivation was paralleled by decreased neuronal death, improved neurological functional deficits and ameliorated cognitive deficits in intracerebral hemorrhage animals. These findings indicate that lithium chloride improves glutamate-mediated excitotoxicity-induced cognitive deficits after intracerebral hemorrhage and that lithium chloride might be a potential therapeutic agent for brain damages caused by intracerebral hemorrhage.

Topics: Animals; Cerebral Hemorrhage; Cognitive Dysfunction; Glycogen Synthase Kinase 3 beta; Hippocampus; Intercellular Signaling Peptides and Proteins; Lithium Chloride; Male; Memory; Nerve Tissue Proteins; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spatial Learning

Application of lithium induces neurogenesis in the damaged brain in the global cerebral ischemia rat model. In a previous study of rats subjected to intracerebral hemorrhage (ICH), we have found that lithium treatment improves functional recovery and reduces acute brain swelling. In this follow-up study, we investigate whether the known beneficial effect of lithium on functional recovery after ICH can be explained by neurorestorative effect.. Intracerebral hemorrhage was induced using infusion of collagenase into the striatum in adult rats. Rats were treated by intraperitoneal injection with lithium chloride (1, 2, or 4 mEq/kg/day) or saline for 2 weeks leading to and 2 weeks following ICH induction. From post-ICH days 4-14, 5-bromo-20-deoxyuridine (BrdU) was administered daily. At 2 weeks post-ICH, immunohistochemical staining was performed for BrdU and doublecortin (Dcx).. The neurological scores for lithium-treated rats improved significantly at 2 weeks post-ICH compared to saline-treated rats. In the subgranular zone (SGZ) and lateral subventricular zone (SVZ), numbers of BrdU-positive cells were not significantly different between the saline-treated and pooled lithium-treated groups. No significant differences in numbers of BrdU-positive cells in the SVZ were detected between the saline-treated and any of the lithium-treated groups. No significant differences in numbers of BrdU-positive cells in the SGZ were detected between the saline-treated and 1 mEq/kg lithium-treated group. Rats treated with ≧ 2 mEq/kg lithium had lower numbers of BrdU-positive cells in the SGZ than did rats treated with saline, although this difference was not statistically significant. Numbers of Dcx-positive cells in the medial striatum were not significantly different between the 1 mEq/kg lithium-treated and saline-treated groups.. The present study shows that lithium does not enhance neurogenesis after ICH in rats, and high dose lithium suppresses neurogenesis in the SGZ. Functional recovery after ICH may be attributable to neuroprotective effect, not neuroregenerative effect of lithium.

Topics: Animals; Bromodeoxyuridine; Cell Proliferation; Cerebral Hemorrhage; Corpus Striatum; Dentate Gyrus; Doublecortin Domain Proteins; Doublecortin Protein; Hippocampus; Lithium Chloride; Male; Microtubule-Associated Proteins; Neurogenesis; Neurons; Neuropeptides; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Recovery of Function; Severity of Illness Index; Treatment Outcome