Investigation of the role of BMAL1 in acute and subacute period traumatic brain injury

Travmatik beyin hasarı, her yıl dünya çapında 50 milyondan fazla bireyi etkilemekle beraber bireylerde kalıcı ve geçici fiziksel etkilerin, nörolojik ve psikolojik sorunların da başlıca nedenlerinden biridir. İnsidansı yüksek olmasına rağmen şu anda Amerikan Gıda ve İlaç Dairesi (FDA) onaylı bir tedavi metodu bulunmamaktadır. Bmal1, sirkadiyen ritmin düzenlemesinde merkezi rol oynayan bir transkripsiyon faktörüdür. Parkinson, beyin felci gibi nörodejeneratif hastalıklarda etkili olan Bmal1'in, beyin hasarı ile meydana gelen mekanizmaların oluşmasını engellemeye yardımcı olduğu düşünülmektir. Bmal1'in travma sonrası meydana gelen moleküler mekanizmalar üzerine etkisi henüz tam aydınlatılamamıştır. Bu tezde Bmal1'in travmatik beyin hasarı patofizyolojisindeki rolünün gösterilmesi amaçlanmıştır. Bu amaçla lentivirüslerle Bmal1 ifadesi arttırılan veya azaltılan farelere soğuk ile indüklenen travmatik beyin hasarı uygulanmıştır. Bmal1 ifadesinin arttılmasının nöronal sağkalımı arttırdığı, apoptotik hücre ölümünü, hasar hacmini ve beyin ödemini azalttığı; Bmal1 ifadesinin azaltılmasının ise nöronal sağkalımı azalttığı, apoptotik hücre ölümünü, hasar hacmini ve beyin ödemini arttırdığı gösterilmiştir. Bmal1'in travmatik beyin hasarı sonrası p-Akt, p-Erk 1/2, p-SAPK/JNK 1/2, Bax, Bcl-XL, eNOS gibi hücresel sağkalımda, stres yanıtlarında, apoptotik mekanizmalarda görev alan ve Gap43, Brevican, Versican gibi aksonal büyüme ile ilgili proteinlere istatiksel anlamlı bir etkisinin olduğu, depresyon, lokomotor aktivite ve motor koordinasyon üzerine ise herhangi istatiksel anlamlı bir etkisi olmadığı gösterilmiştir. Elde edilen sonuçların literatürde lentiviral vektörler aracılığıyla protein ifadesi arttırılmış ve azaltılmış olan Bmal1'in hem akut dönem hem de subakut dönem travmatik beyin hasarı sonrası etkisinin aydınlatılmasına katkı sağlaması beklenilmektedir.Traumatic brain injury affects more than 50 million individuals worldwide each year, and is one of the main causes of permanent and temporary physical effects, neurological and psychological problems in individuals. Despite the incidence is high, there is currently no specific treatment method approved by the US Food and Drug Administration (FDA). Bmal1 is a transcription factor that plays a central role in the regulation of the circadian rhythm. Bmal1 is known to play a role in neurodegenerative diseases such as Parkinson's and stroke, it is thought to help prevent the formation of mechanisms that occur with brain damage. The effect of Bmal1 on the molecular mechanisms that occur after trauma has not yet been fully elucidated. In this thesis, it is aimed to show the role of Bmal1 in the pathophysiology of traumatic brain injury. For this purpose, cold-induced traumatic brain injury was applied to mice which have increasing or decreasing Bmal1 expression induced by lentiviruses. According to the results, increased Bmal1 expression increased neuronal survival, decreased apoptotic cell death, injury volume, and brain edema; it has been observed that decreasing Bmal1 expression decreases neuronal survival, increases apoptotic cell death, injury volume and brain edema. A statistically significant effect of Bmal1 on proteins that play a role in cellular survival, stress responses and apoptotic mechanisms such as p-Akt, p-Erk 1/2, p-SAPK/JNK 1/2, Bax, Bcl-XL, eNOS after traumatic brain injury. It has been shown that it has a statistically significant effect on axonal growth-related proteins such as Gap43, Brevican, Versican, but has no statistically significant effect on depression, locomotor activity and motor coordination. It is expected that the results obtained will contribute to the elucidation of the effect of Bmal1, whose protein expression is increased and decreased by lentiviral vectors in the literature, after both acute and subacute traumatic brain injury

The role of phosphatidylinositol-3 kinase/AKT and ERK-1/2 pathways in the neuroprotective activity of lithium

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The unconventional growth factors cerebral dopamine neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor promote post-ischemic neurological recovery, perilesional brain remodeling, and lesion-remote axonal plasticity

Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3 days post-stroke (1 mu g/day for 28 days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1 beta and TNF alpha in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.Turkish Academy of Science