THE SEARCH FOR NEUROPROTECTIVE COMPOUNDS AMONG NEW ETHYLTHIADIAZOLE DERIVATIVES

The aim of the study is to search compounds with neuroprotective properties among new ethylthiadiazole derivatives in simulated traumatic brain injury.Materials and methods. The experiment was carried out on 78 white male rats 270±20 g line “Wistar” 5–6 months of age and 120 outbred sexually mature mice weighing 20±2 grams. The article describes the search for compounds with neuroprotective properties among new ethylthiadiazole derivatives under the codes LKHT 4–15, LKHT 10–18, LKHT 11–18, and LKHT 12–18 in experimental traumatic brain injury in rats. Acute toxicity of the compounds was studied. Pharmacological screening was performed using behavioral and neurological research methods. The McGraw stroke score scale modified by I.V. Gannushkina and the mNSS psychometric scale were used in the study. The open field and Rota-rod tests were used to assess the behavioral status of the animals.Results. The compound-LKHT 12–18 at a dose of 50 mg/kg was detected as a leader. In pharmacological correction of pathology, this compound had the lowest percentage of fatality among the studied compounds (8%), the severity of neurological deficit was significantly reduced, the lowest scores and a higher level of motor activity of the limbs were registered. The number of rearing in the group of animals receiving the compound LKHT 12–18 at the dose of 50 mg/kg increased by 1.5 times, statistically significant (p<0.05) in comparison with the control group. Based on the results of the “Rota-rod” test, the total time of holding animals on the rod for 3 attempts was statistically significantly different in the groups administered with LKHT 12–18 derivatives (1.5 times longer) at the dose of 50 mg/kg compared with the control (p<0.05).Conclusion. Based on the results obtained in this study, it is planned to study in more detail the compound LKHT 12–18 at the dose of 50 mg/kg.

Inhibited CSF1R Alleviates Ischemia Injury via Inhibition of Microglia M1 Polarization and NLRP3 Pathway

Ischemia cerebral stroke is one of the common neurological diseases with severe inflammatory response and neuron death. The inhibition of colony-stimulating factor 1 receptor (CSF1R) which especially expressed in microglia/macrophage exerted neuroprotection in stroke. However, the underlying neuroinflammatory regulation effects of CSF1R in ischemia stroke are not clear. In this study, cerebral ischemia stroke mice model was established. The C57/B6J mice were administered with Ki20227, a CSF1R inhibitor, by gavage for 7 consecutive days (0.002 mg/kg/day) before modeling. The Rota-Rod test and neurobehavioral score test were investigated to assess neurobehavioral functions. The area of infarction was assessed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The mRNA expressions of M1/M2 microglia markers were evaluated by real-time PCR. Immunofluorescence and Western blot were utilized to detect the changes of Iba1 and NLRP3 pathway proteins. Results showed that neurobehavioral function improvement was demonstrated by an increased stay time on the Rota-Rod test and a decreased neurobehavioral score in the Ki20227 treatment group. The area of infarction reduced in Ki20227 group when compared to the stroke group. Moreover, the mRNA expression of M1 microglia markers (TNF-α and iNOS) decreased while M2 microglia markers (IL-10 and Arg-1) increased. Meanwhile, compared to the stroke and stroke+PBS group, Ki20227 administration downregulated the expression of NLRP3, active caspase 1, and NF-κB protein in the ischemia penumbra of Ki20227 treatment group mice. In short, the CSF1R inhibitor, Ki20227, played vital neuroprotective roles in ischemia cerebral stroke mice, and the mechanisms may be via inhibiting microglia M1 polarization and NLRP3 inflammasome pathway activation. Our study provides a potential new target for the treatment of ischemic stroke injury.

Hypnotic activity of Capparis spinosa hydro-alcoholic extract in mice

Background: Sleep disorders are among the most common psychiatric and medical conditions. Objective: The present study aimed at investigating the hypnotic activity of the hydro-alcoholic extract of Capparis spinosa (HAE) in mice. Method: Three doses of HAE (30, 60 and 120 mg/kg) and three fractions of it, namely n-hexane fraction (NHF), water fraction (WF), and ethyl acetate fraction (EAF), were given in comparison with diazepam (3mg/kg body weight i.p.) as positive control and saline as negative control. After 30 min, pentobarbital (30 mg/kg body weight i.p.) was administrated. In addition, LD50 of HAE was examined and the cytotoxicity of HAE was assessed in l929 cells using the MTT assay. Moreover, for motor-coordination ability 30 mins after administration of HAE rota-rod test was performed. Results: The results exhibited that the HAE and all the fractions significantly augmented pentobarbital induced sleeping time which was comparable to that of induced by diazepam. The LD50 value was 2.4 g/kg. The extract did not induce any cytotoxic effects in L929 fibroblast cells. HAE did not affect the animals’ performance on the rota-rod test. Conclusion: Our finding suggests that hydro-alcoholic extract of C. spinosa possesses hypnotic potential that may require further scientific investigations.

The Motor Coordination Activity Of Aqueous Extract Of Withania Coagulans Fruits In Swiss Albino Mice By Rota Rod Test

Background: The various sedative and hypnotic medications used today have the central nervous system (CNS) depressant effects. A very little work has been done on the Withania coagulans – a vulnerable species as it is not found rampant in the world except in late seventies. Therefore, it was important to explore the CNS depressant activities of aqueous extract of Withania coagulans fruits in Swiss albino mice by using rota rod test. Methods: Motor coordination was assessed by using the Rota Rod Test. The CNS depressant drugs decrease the endurance time of mice on the rota rod as they impair the motor coordination so that mice fall early on the rotating rod. This endurance time is statistically correlated among the control, standard and the test drugs. Results: There was statistically highly significant (p-value < 0.001) association observed between aqueous extract of Withania coagulans fruits with endurance time in Swiss albino mice on rota rod test. Conclusion: The aqueous extract of Withania coagulans fruits demonstrated the CNS depressant activity in Swiss albino mice by rota rod test.

Fractions of Selaginella convoluta (Arn.) Spring (Selaginellaceae) attenuate the nociceptive behavior events in mice

Selaginella convoluta (Arn.) Spring is a species popularly known as “jericó”, and used in folk medicine as analgesic and anti-inflammatory. This study aimed to investigate in mice the antinociceptive and anti-inflammatory activities of the hexane (Sc-Hex) and chloroform (Sc-CHCl3) fractions (100, 200 and 400 mg/kg) obtained by partition of crude ethanol extract from S. convoluta. The preliminary phytochemical analysis of the fractions was performed. Antinociceptive activity was evaluated by writhing, formalin and hot-plate tests. Anti-inflammatory activity was evaluated using carrageenan-induced pleurisy. The rota-rod test was used to evaluate motor coordination. Preliminary phytochemical screening showed that the Sc-Hex and the Sc-CHCl3 were positive for the presence of flavonoids, anthracene derivatives, quinones, triterpenes and steroids. Inhibition of writhing was observed for fractions tested. The Sc-Hex at all doses tested was effective in reducing the nociceptive behavior produced by formalin only in the second phase. However, the Sc-CHCl3 decreased the paw licking time in the first and second phases. In the hot plate no significant effect was observed for any fraction. In the rota-rod test, treated mice did not demonstrate any significant motor performance changes. In the carrageenan-induced pleurisy, Sc-CHCl3 (200 mg/kg) reduced cell migration to the pleural cavity. These results reveal the antinociceptive properties of S. convoluta , which support, in part, its traditional use, since the fractions did not presented significant activity in the inflammatory response profile. We further verify that this antinociceptive effect could be by activation of nociceptive peripheral pathway.

Aktivitas Antiparkinson Ekstrak Rosella (Hibiscus Sabbdariffa L.) Pada Tikus Putih Jantan (Rattus Norvegicus) Galur Sprague Dawley Yang Diinduksi Haloperidol

Penyakit parkinson merupakan penyakit yang disebabkan karena penurunan kadar dopamin pada pars compacta substantia nigra. Dopamin erat kaitannya dengan antioksidan, karena antioksidan dapat mengurangi radikal bebas yang merusak sel-sel penghasil dopamin. Rosella adalah salah satu tanaman yang mempunyai kandungan antioksidan yaitu flavonoid, saponin, dan alkaloid. Tujuan penelitian ini adalah untuk mengetahui pengaruh ekstrak rosella terhadap penurunan gejala penyakit parkinson.Penelitian ini menggunakan hewan uji tikus putih galur Sprague dawley sebanyak 35 ekor, tikus dibagi menjadi 7 kelompok. Kelompok I (kontrol sehat) diberi aquadestillata p.o, kelompok II (kontrol negatif) diberi CMC-Na 0,5 % p.o, kelompok III (kontrol positif I) diberi levodopa 27 mg/kgbb p.o, kelompok IV (kontrol positif II) diberi vitamin E 180 IU/kgbb tikus p.o. Kelompok V, VI, dan VII diberi ekstrak rosella dosis berturut-turut 150; 300; 600 mg/kgbb p.o. Seluruh kelompok diinduksi dengan haloperidol pada menit ke-45 setelah perlakuan kecuali pada kelompok I (kontrol sehat). Kemudian diuji dengan catalepsy bar test, dicatat waktu latensi yang dinyatakan dalam skor dan rota rod test, dicatat waktu latensi dalam detik pada hari ke 0, 4, 7, 11, dan 14.Hasil penelitian menunjukkan bahwa ekstrak rosella memberikan efek antiparkinson pada tikus putih galur Sprague dawley yang diinduksi haloperidol. Dosis efektif rosella dalam menurunkan gejala parkinson adalah 300 mg/kg bb

Aktivitas Antiparkinson Ekstrak Gambir (Uncaria Gambir Roxb.) Pada Tikus Putih (Rattus Norvegicus) Galur Sprague Dawley yang Diinduksi Haloperidol

Parkinson merupakan penyakit yang terjadi akibat adanya kerusakan sel saraf dopaminergik pada bagian otak yang mengakibatkan terjadinya penurunan produksi dopamin. Gambir adalah ekstrak kering yang dibuat dari daun tumbuhan Uncaria gambir Roxb. Gambir mengandung flavonoid berupa katekin tidak kurang dari 90%, alkaloid dan terpenoid. Penelitian ini bertujuan untuk mengetahui aktivitas ekstrak gambir yang dapat mengurangi gejala parkinson pada tikus putih jantan galur Sprague dawley yang diinduksi haloperidol.Hewan uji sebanyak 35 ekor tikus dibagi menjadi 7 kelompok. Kelompok I (kontrol sehat) diberi aquadest secara per oral, kelompok II (kontrol negatif) diberi larutan CMC-Na 0,5 % p.o, kelompok III (kontrol positif I) diberi levodopa 27 mg/kgbb p.o, kelompok IV (kontrol positif II) diberi vitamin E 180 IU/kgbb p.o. Kelompok V, VI, dan VII diberi ekstrak gambir dosis berturut-turut 70; 140; 280 mg/kgbb. Seluruh kelompok diinduksi haloperidol 2 mg/kgbb i.p pada menit ke-45 setelah perlakuan kecuali pada kelompok sehat. Kemudian kelompok diuji dengan catalepsy bar test, dicatat waktu latensi yang dinyatakan dalam skor dan rota rod test, dicatat waktu latensi dalam detik pada hari ke 0, 4, 7, 11, dan 14.Hasil penelitian menggunakan metode catalepsy bar test menunjukkan % penurunan katalepsi pada ekstrak gambir dosis 70; 140; 280 mg/kgbb mempunyai aktivitas yang berturut-turut sebesar 22,53; 52,50; 57,12 %. Sedangkan hasil dengan metode rota rod test menunjukkan % kenaikan waktu latensi ekstrak gambir berturut-turut sebesar 27,69; 35,75; 39,61 %.

Synthesis, Anticonvulsant and Neurotoxicity Screening of Some Novel 2, 5-Disubstituted - 1, 3, 4 � Oxadiazole Derivatives

A series of 2, 5-disubstituted - 1, 3, 4 oxadiazoles (4a-o) were synthesized on refluxing hydrazine carbothioamides with iodine and potassium iodide in ethanolic sodium hydroxide solution starting from methyl-3-amino-4-hydroxy benzoate via synthesis of an intermediate methyl-2-substitutedaryl-1, 3-benzoxazole-5-carboxylates and 2-substitutedaryl-1, 3-benzoxazole-5-carbohydrazides. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, 1H-NMR, MS) and elemental analysis. All these compounds were screened for anticonvulsant activity using Maximal Electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) method. Anticonvulsant activity was shown by majority of the synthesized compounds when given i.p. to mice. Among the tested compounds 4e, 4j and 4o were considered to have potent anticonvulsant activity comparable to that of standard drugs Phenytoin and Carbamazepine. Compounds 4e, 4g, 4h, 4i, 4k and 4m passed the rota rod test successfully without any sign of neurological deficit.

The Effect of Carvacrol on Inflammatory Pain and Motor Coordination in Rats

Carvacrol is a monoterpenic phenol and an active ingredient of the plant essential oils of the family Lamiaceae. We have investigated the analgesic effect of carvacrol, the possible dependence of the effect in relation to animal sex, and the impact of carvacrol on motor coordination in rats. Hyperalgesia was induced by formalin (1.5%), which was administered SC in the upper lip of rat. Hyperalgesia and effects of carvacrol and indomethacin were measured by using the orofacial formalin test. The influence on motor coordination in animals treated with carvacrol was investigated by using the rota-rod test. Carvacrol administered PO in pre-treatment (45 min. prior to formalin) at a single dose of 50, 75 and 100 mg /kg BW, in the male, 50 and 100 mg /kg BW, in female rats caused a dose-dependent antinociceptive effect. This effect of carvacrol was significantly higher (P<0.01, P<0.001) in male rats. Compared with indomethacin administered during pre-treatment (2 mg/kg, PO), carvacrol (100 mg/kg) exhibits significantly higher (P <0.05 and P <0.001) antinociceptive effect on formalininduced hyperalgesia in male rats. In the rota-rod test carvacrol did not disturb the motor coordination in male rats, nor the dose of carvacrol with clear antinociceptive properties exhibited depressive effect on the CNS of treated rats. Keeping in mind that the monoterpene carvacrol is of plant origin, with potentially less side effects and without residues, it is realistic to expect the possibility of its therapeutic use in the treatment of inflammatory pain in animals.