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Glutamate is the most abundant excitatory neurotransmitter in the central nervous system. Through its ionotropic and metabotropic receptors it mediates both fast transmission and long term metabolic changes in a cell. Besides neurotransmission, it takes part in development of central nervous system, cell energy metabolism and synaptic plasticity processes. Glutamatergic signaling is strictly controlled. Under normal conditions, extrasynaptic gluatamate levels are maintained at low concentrations. Excessive transmission leads to excitotoxicity which results in cell damage and death. Glutamatergic dysfunction is involved in many pathologies including neuropsychiatric, neurodegenerative and neurodevelopmental disorders. Impairments in glutamate’s physiological functions, excitotoxicity and disrupted modulation of other neurotranmitter systems contribute to these pathologies. This opinion aims to summarize the cellular mechanism that lead to pathology and review how these mechanisms translate into the clinic.

Objective: Our aim was to investigate the relation between unilateral hippocampal and/or nigral alpha-synucleinopathy and cognitive dysfunction, anxiety and anhedonia. Materials and Methods: Female Sprague-Dawley rats were stereotactically injected adeno-associated viruses carrying alpha-synuclein (α-syn) into unilateral dentate gyrus (DG), substantia nigra (SN) or both SN + DG. The animals were tested for motor functions and memory, spatial learning, anxiety and hedony. Levels of α-syn and synaptophysin were evaluated by Western blot (WB) analysis. Results: In apomorphine-induced rotation test, a mild motor dysfunction was found in SN-α-syn group compared to control. DG- α-syn group showed memory impairment in novel object recognition test. All the α-syn injected groups spent more time to find the platform compared to controls in Morris water maze but this difference did not reach statistical significance. DG-α-syn group consumed more sucrose solution in sucrose consumption test and spent more time on the open arm in elevated plus maze, while the opposite was observed in SN-α-syn group compared to controls. We showed α-syn protein expression in the injected areas of all α-syn groups by WB and immunohistochemical staining. In WB analysis, both hippocampal and striatal synaptophysin expression levels were lower in the α-syn groups compared to controls. Conclusion: Parkinson’s disease (PD) is characterized by both motor and non-motor symptoms (NMS). However, an animal model recapitulating NMS with the background of dopaminergic denervation is still lacking. This model may help to investigate hippocampal α-syn pathology correlated especially with cognitive dysfunction and other NMS of PD.

In cancer treatment, conventional chemotherapeutics have been in clinical use since 1940s. Even though their efficacy has been established for many years, selectivity problem and serious side effects limit their use. Disadvantages of available therapies and need for novel anti-cancer drugs induced a shift in research towards that direction. Over the past 20 years, by shedding light onmolecular mechanisms of cancer, intracellular proteins, that might be targets for new drugs, have been defined. Of these targets, primary ones are; PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, Ubiquitin-Proteasom and Hedgehog pathways. These pathways and their downstream effectors shown to play a role in many cancer types. Protein kinases, which are involved in intracellular signaling pathways and found to be related to those pathways, are the molecules that are most studied. Many inhibitor molecules and/or monoclonal antibodies spesific to tyrosine and serine/theronine kinases have been developed and brought into use. Several members of tyrosine kinase family, which consists of around 20 subclasses, have been shown to be related to cancer. In this regard, prominent receptor tyrosine kinases can be sorted as EGFR, PDGFR, VEGFR, FLT3 and ALK. Other protein kinases; Src, BTK, CDK and AMPK have been reported to mediate critical processes in cancer development. Beside those targets, potential molecular targets and chemotherapeutic agents to these targets have been defined. Many molecules, that were developed to inhibit NOTCH, JAK-STAT, Nuclear Factor Kappa B, Wnt/ ß-Catenin pathways, Insulin, FGF, HGF, GSK-3 receptors, Protein Kinase C, Aurora Kinase and Hsp90 activity, are in stage of clinical study., Kanser tedavisinde, konvansiyonel kemoterapötikler 1940’lı yıllardan beri klinikte kullanılmaktadırlar. Etkililikleri uzun yıllardır kanıtlanmış olsa da seçicilik sorunu ve ciddi yan etkilere yol açmaları bu ajanların kullanımını kısıtlar. Mevcut tedavilerin dezavantajları ve yeni anti-kanser ilaçlarına olan ihtiyaç araştırmaların bu yöne kaymasına neden olmuştur. Son 20 yılda kanserinmoleküler mekanizmalarının da aydınlatılması ile yeni ilaçlar için hedef olabilecek proteinler tanımlanmıştır. Bu hedeflerden başlıcaları PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, Ubikitin-Proteazom ve Hedgehog yolaklarıdır. Bu yolakların ve efektörlerinin birçok kanser tipinde rolü olduğu gösterilmiştir. Hücre içi sinyal mekanizmalarında görev alan ve bu yolaklarla ilişkili bulunan proteinkinazlar üzerlerinde en çok çalışma yapılan moleküllerdir. Tirozin ve serin/treonin kinazlara özgü birçok inhibitör molekül ve/veya monoklonal antikor geliştirilmiş ve kullanıma sunulmuştur. Yaklaşık 20 alt sınıftan oluşan reseptör tirozin kinazların (RTK) birçok üyesinin kanserle ilişkili olduğu gösterilmiştir. Bu bağlamda öne çıkan RTK’lar; EGFR, PDGFR, VEGFR, FLT3 ve ALK olarak sıralanabilir. Diğer protein kinazlardan Src, BTK, CDK ve AMPK’nın kanser gelişimi ile ilgili kritik süreçlere aracılık ettiği bildirilmiştir. Bu hedeflerin yanısıra potansiyel moleküler hedefler ve bu hedeflere yönelik kemoterapötik ajanlar da belirlenmiştir. NOTCH, JAK-STAT, Nükleer Faktör Kappa B, Wnt/ ß-Catenin yolaklarını, İnsülin, FGF, HGF, GSK-3 reseptörlerini, Protein Kinaz C, Aurora Kinaz ve Hsp90 aktivitesini inhibe etmeye yönelik geliştirilen birçok molekül klinik çalışma aşamasındadır.