1.Brain α7 nicotinic acetylcholine receptors in MPTP-lesioned monkeys and parkinsonian patients.
Morissette M1, Morin N2, Grégoire L3, Rajput A4, Rajput AH5, Di Paolo T6. Biochem Pharmacol. 2016 Mar 30. pii: S0006-2952(16)30004-1. doi: 10.1016/j.bcp.2016.03.023. [Epub ahead of print]
L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson's disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain α7 nACh receptors might be a potential therapeutic target for PD. This study used [125I]α-Bungarotoxin autoradiography to investigate α7 nACh receptors in LID in post-mortem brains from PD patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [125I]α-Bungarotoxin specific binding to striatal and pallidal α7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding.
2.4-Organoseleno-Isoquinolines Selectively and Reversibly Inhibit the Cerebral Monoamine Oxidase B Activity.
Sampaio TB1, Da Rocha JT2, Prigol M3, Saraiva RA4, Nogara PF1, Stein AL1, da Rocha JB1, Zeni G1, Nogueira CW5. J Mol Neurosci. 2016 Apr 6. [Epub ahead of print]
Isoquinolines are formed endogenously as metabolites of neurotransmitters and are studied because they have structures similar to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and selegiline, a selective inhibitor of MAO-B. This study investigated a possible in vitro inhibitory activity of new 4-organochalcogen-isoquinoline derivatives, containing sulfur 1, selenium 2 or tellurium 3 on MAO-A and B activities. Considering that the non-substituted selenoisoquinoline derivative 2 showed the best inhibitory profile (IC50 = 36.45 μM), new compounds were synthesized by adding substituents (methyl 2a, fluorine 2b, chloro 2c and trifluoromethyl 2d) to the aromatic ring bonded to the selenium atom of compound 2. All tested compounds were selective MAO-B inhibitors, although only the substituted isoquinoline derivative 2b showed IC50 lower than the concentration of 100 μM (IC50 = 82.41 μM). Compounds 2 and 2b were chosen to study the inhibitory profile.
3.Synthesis of some tetrahydropyrimidine-5-carboxylates, determination of their metal chelating effects and inhibition profiles against acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase.
Sujayev A1, Garibov E1, Taslimi P2, Gulçin İ2,3, Gojayeva S1, Farzaliyev V1, Alwasel SH3, Supuran CT4,5. J Enzyme Inhib Med Chem. 2016 Mar 28:1-9. [Epub ahead of print]
2-(Methacryloyloxy)ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate, is a cyclic urea derivative synthesized from urea, 2-(methacryloyloxy) ethyl acetoacetate and substituted benzaldehyde, and tested in terms of the inhibition of two physiologically relevant carbonic anhydrase (CA) isozymes I and II. Acetylcholinesterase (AChE) is found in high concentrations in the red blood cells and brain. Butyrylcholinesterase (BChE) is another enzyme abundantly present in the liver and released into blood in a soluble form. Also, they were tested for the inhibition of AChE and BChE enzymes and demonstrated effective inhibition profiles with Ki values in the range of 429.24-530.80 nM against hCA I, 391.86-530.80 nM against hCA II, 68.48-97.19 nM against AChE and 104.70-214.15 nM against BChE. On the other hand, acetazolamide clinically used as CA inhibitor, showed Ki value of 281.33 nM against hCA I, and 202.70 nM against hCA II.
4.Mitochondrial Ferritin Suppresses MPTP-induced Cell Damage by Regulating Iron Metabolism and Attenuating Oxidative Stress.
You LH1, Li Z1, Duan XL1, Zhao BL1, Chang YZ2, Shi ZH3. Brain Res. 2016 Mar 23. pii: S0006-8993(16)30152-4. doi: 10.1016/j.brainres.2016.03.023. [Epub ahead of print]
Our previous work showed that mitochondrial ferritin (MtFt) played an important role in preventing neuronal damage in 6-OHDA-induced Parkinson's disease (PD). However, the role of MtFt in a PD model induced by MPTP is not clear. Here, we found that methyl-4-phenyl-1, 2, 3, 6-tetra-pyridine (MPTP) significantly upregulated MtFt in the mouse hippocampus, substantia nigra (SN) and striatum. To explore the effect of MtFt upregulation on the MPTP-mediated injury to neural cells, MtFt-/- mice and MtFt-overexpressing cells were used to construct models of PD induced by MPTP. Our results showed that MPTP dramatically downregulated expression of transferrin receptor 1 (TfR1) and tyrosine hydroxylase and upregulated L-ferritin expression in the mouse striatum and SN. Interestingly, MPTP induced high levels of MtFt in these tissues, indicating that MtFt was involved in iron metabolism and influenced dopamine synthesis induced by MPTP. Meanwhile, the Bcl2/Bax ratio was decreased significantly by MPTP in the striatum and SN of MtFt knockout (MtFt-/-) mice compared with controls.