Lithium promotes long-term neurological recovery after spinal cord injury in mice by enhancing neuronal survival, gray and white matter remodeling, and long-distance axonal regeneration

Spinal cord injury (SCI) induces neurological deficits associated with long-term functional impairments. Since the current treatments remain ineffective, novel therapeutic options are needed. Besides its effect on bipolar mood disorder, lithium was reported to have neuroprotective activity in different neurodegenerative conditions, including SCI. In SCI, the effects of lithium on long-term neurological recovery and neuroplasticity have not been assessed. We herein investigated the effects of intraperitoneally administered lithium chloride (LiCl) on motor coordination recovery, electromyography (EMG) responses, histopathological injury and remodeling, and axonal plasticity in mice exposed to spinal cord transection. At a dose of 0.2, but not 2.0 mmol/kg, LiCl enhanced motor coordination and locomotor activity starting at 28 days post-injury (dpi), as assessed by a set of behavioral tests. Following electrical stimulation proximal to the hemitransection, LiCl at 0.2 mmol/kg decreased the latency and increased the amplitude of EMG responses in the denervated hindlimb at 56 dpi. Functional recovery was associated with reduced gray and white matter atrophy rostral and caudal to the hemitransection, increased neuronal survival and reduced astrogliosis in the dorsal and ventral horns caudal to the hemitransection, and increased regeneration of long-distance axons proximal and distal to the lesion site in mice receiving 0.2 mmol/kg, but not 2 mmol/kg LiCl, as assessed by histochemical and immunohistochemical studies combined with anterograde tract tracing. Our results indicate that LiCl induces long-term neurological recovery and neuroplasticity following SCI.TUBA ; Istanbul Medipol University ; Turkish Academy of Science

Investigation of the effects of lithium after long-term spinal cord damage

Omurilik hasarı, sinir ağlarında meydana gelen nörolojik hasara ve fonksiyonel kayıpların oluşmasına neden olmaktadır. Hasara yönelik tedavi yöntemleri hasarın neden olduğu dejeneratif etkileri azaltmada yetersizdir. Omurilik hasarı sonrası rejenerasyon ve nöroproteksiyon hedefli etkili çalışmalar günümüzde yeterli derecede değildir. Bu nedenle etkili ve yeni terapötik odaklı çalışmaların yapılması gerekmektedir. Bipolar bozukluk için terapötik etki gösteren lityumun nörodejeneratif rahatsızlıkların tedavisinde protektif etki gösterdiği bilinmesine rağmen lityumun omurilik hasarı sonrası uzun dönemdeki iyileşmeye yönelik etkisi tam olarak bilinmemektedir. Bu bilinmezlikten yola çıkılarak bu tezde omurilik yarı kesi hasar modeli oluşturulan farelerde hasar sonrası farklı dozlarda uygulanan lityumun doza bağlı fonksiyonel geri kazanım açısından etkisi incelenmiştir. Terapötik lityum konsantrasyonunun hasar sonrası doku atrofisine, nöronal sağkalıma, glial hücreler üzerindeki etkisine ve aksonal plastisiteye yönelik etkileri incelenmiştir. Elde edilen sonuçlara göre foksiyonel gezi kazanım açısından 0.2 mmol/kg lityum uygulanmasının, hasardan 28 gün sonra sağ taraflı hemiplejik farelerin az olan lokomotor aktivitelerinde iyileşme sağladığı gözlenmiştir. Elektromiyografi yöntemi sonuçlarında, hasar sonrası uygulanan lityumun hemiplejik taraftaki gastrokinemius kası üzerinde uyarım sonrası sinyal iletimine ve kontraksiyona yönelik terapötik etki gösterdiği gözlenmiştir. Ayrıca lityum hasar alanındaki lezyon hacmini azaltıcı etki göstermiştir. 0.2 mmol/kg dozundaki lityum omuriliğin rostral segmentindeki atrofiyi azaltmış ve nöronlar üzerinde protektif etki göstermiştir. Lityum uygulaması glial hücre sayısını azaltıcı etki göstermekle birlikte, hasar sonrası dejenere olan aksonal yolakların rejenerasyonunu destekleyici etki göstermiştir. Sonuçlara göre, lityum tedavisinin omurilik hasarının dejeneratif etkilerine karşılık yeni ve etkili terapötik bir katkı sağlaması beklenilmektedir.Spinal cord injury causes neurological damage and functional loss in neural networks. Damage-oriented treatment methods are insufficient to reduce the degenerative effects. Effective studies targeting regeneration and neuroprotection after spinal cord injury are not sufficient today. Therefore, it is necessary to carry out effective and new therapeutic-oriented studies. Although it is known that lithium, is used for treatment of disorder, and has a protective effect in the treatment of neurodegenerative disorders, the effect of lithium on long-term recovery after spinal cord injury is not fully known. Based on this uncertainty, in this thesis, the effect of lithium administered at different doses in mice with a spinal cord half-incision injury model in terms of dose-dependent functional recovery was investigated. The effects of therapeutic lithium concentration on tissue atrophy, neuronal survival, effect on glial cells, and axonal plasticity after injury were investigated. It was observed that 0.2 mmol/kg lithium administration after injury improved the locomotor activities, which were less in right-sided hemiplegic mice 28 days after injury, in terms of functional excursion gain. According to the electromyography, lithium administration after injury, has a therapeutic effect on post-stimulation signal transmission and contraction on the gastrocnemius muscle on the hemiplegic side. As a result of the studies, lithium shows the effect of reducing the lesion volume in the damaged area. Lithium at a dose of 0.2 mmol/kg showed a reducing effect on atrophy due to damage in the rostral segment of the spinal cord and showed a protective effect on neurons. Lithium administration showed a decreasing effect on the number of glial cells, but it also showed a supportive effect on the regeneration of degenerated axonal pathways after damage. According to the results, it is expected that lithium treatment in the chronic period will provide a new and effective therapeutic contribution to the degenerative effects of spinal cord injury

Effects of repetitive transcranial magnetic stimulation (rtms) on post-brain stroke damage

Repetatif transkraniyal manyetik stimülasyon (rTMS) tedavisi invazif olmayan, frekansı uyarıcı veya inhibe edici olmak üzere ayarlanabilen, beyin felci sonrası hemisferler arası düzeni tekrar sağlayan tedavi yöntemidir. Her ne kadar rTMS tedavisi klinikte sıklıkla kullanılsa da rTMS uygulamasının etki ettiği moleküler mekanizma tam olarak bilinememektedir. Beyin felci gelişmekte olan ülkelerde 2. ölüm sebebidir. rTMS tedavisinin, beyin felci sonrası moleküler mekanizmalardaki etkilerini araştırmak için 90 dakika orta serebral arter tıkanması modeli BALB/c farelerde oluşturuldu. Reperfüzyon başlangıcında uygulanan rTMS tedavisinin serebral kanlanma, hasar hacmi, ve gen ekspresyon değişiklikleri üzerindeki etkileri incelendi. Deney gruplarına 1 Hz inhibe edici, 20 Hz uyarıcı etki gösteren rTMS tedavisi uygulandı. Kontrol grubu rTMS tedavisi almadı. 20 Hz rTMS tedavisi kontrol grubuna ve 1 Hz grubuna göre iskemik kor bölgesinde, penumbra alanında ve hasarsız kortekste serebral kanlanmayı istatistiksel olarak anlamlı bir şekilde artırdı ve hasar hacmini istatistiksel olarak anlamlı bir şekilde azalttı. 20 Hz rTMS tedavisinin gen ekspresyonunda yaptığı değişiklikler enflamasyonun azaltılmasına, nöroplastisiteye ve vasküler regülasyona katkı sağladığı görüldü. Uygulanan 20 Hz rTMS tedavisinin beyin felci sonrası sonrası gen ekspresyonunu regüle ederek ve serebral kanlanmayı arttırarak hasarı azalttığı düşünülmektedir.Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive treatment method whose frequency is regulated as stimulator or inhibitor, which provides the balance between hemispheres after brain stroke. Although rTMS treatment is often used in clinic, effect of TMS on the molecular mechanism is unknown. Brain stroke is the second cause of death in the developing countries. A 90-minute of middle cerebral artery occlusion was induced in BALB/c mice to investigate the effects of rTMS treatment on molecular mechanism post-stroke. The rTMS treatment was administered at the beginning of reperfusion and the effects of treatment on infarct volume, cerebral blood flow and gene expression changes were examined. Experimental groups were designed as 1 Hz rTMS (inhibitory) application group, 20 Hz rTMS (stimulatory) application group whereas the rTMS treatment was not applied to the control group. 20 Hz rTMS treatment increased the cerebral blood flow in the ischemic core area, penumbra area and undamaged cortex when compared with control group. Also, 20 Hz rTMS treatment reduced the infarct volume. 20 Hz rTMS treatment regulated gene expression that contributes the reduction of inflammation, induction of the neuroplasticity related genes and the vascular regulation. It is believed that by regulating gene expression and increased cerebral blood flow the application of 20 Hz treatment decreased infarct volume

Investigation of the effects of lithium after long-term spinal cord injury

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The effect of lithium on long-term neuronal survival and regeneration after spinal cord injury in mice

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Neuroprotective effect of diet restricted preconditioning on cerebral ischemia in mice

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Effects of repetitive transcranial magnetic stimulation on motor activity and neuronal survival after spinal cord injury

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The effect of Oatp1a5 on drug accumulation and injury upon ischemic stroke

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Phosphorylation of PI3K/Akt at Thr308, but not phosphorylation of MAPK kinase, mediates lithium-induced neuroprotection against cerebral ischemia in mice

Lithium, in addition to its effect on acute and long-term bipolar disorder, is involved in neuroprotection after ischemic stroke. Yet, its mechanism of action is still poorly understood, which was only limited to its modulatory effect on GSK pathway. Therefore, we initially analyzed the dose-dependent effects of lithium on neurological deficits, infarct volume, brain edema and blood-brain barrier integrity, along with neuronal injury and survival in mice subjected to focal cerebral ischemia. Thereafter, we investigated the involvement of the PI3K/Akt and MEK signal transduction pathways and their components. Our observations revealed that 2 mmol/kg lithium significantly improved post-ischemic brain tissue survival. Although, 2 mmol/kg lithium had no negative effect on brain microcirculation, 5 and 20 mmol/kg lithium reduced brain perfusion. Furthermore, supratherapeutic dose of lithium in 20 mmol/kg lead to animal death. In addition, improvement of brain perfusion with L-arginine, did not change the effect of 5 mmol/kg lithium on brain injury. Additionally, post-stroke blood-brain barrier leakage, hemodynamic impairment and apoptosis have been reversed by lithium treatment. Interestingly, lithium-induced neuroprotection was associated with increased phosphorylation of Akt at Thr308 and suppressed GSK-3β phosphorylation at Ser9 residue. Lithium upregulated Erk-2 and downregulated JNK-2 phosphorylation. To distinguish whether neuroprotective effects of lithium are modulated by PI3K/Akt or MEK, we sequentially blocked these pathways and demonstrated that the neuroprotective activity of lithium persisted during MEK/ERK inhibition, whereas PI3K/Akt inhibition abolished neuroprotection. Collectively, we demonstrated lithium exerts its post-stroke neuroprotective activity via the PI3K/Akt pathway, specifically via Akt phosphorylation at Thr308, but not via MEK/ERK.Turkish Academy of Sciences ; Istanbul Medipol Universit