New histopathological evidence for the relationship between hydromyelia and hydrocephalus following subarachnoid hemorrhage: An experimental study.

Objectives: Subarachnoid hemorrhage (SAH) is a serious pathology with a high death and morbidity rate. There can be a relationship between hydromyelia and hydrocephalus following SAH; however, this subject has not been well investigated. Materials and Methods: Twenty-four rabbits (3 ± 0.4 years old; 4.4 ± 0.5 kg) were used in this study. Five of them were used as the control, and five of them as the SHAM group. The remaining animals (n = 14) had been used as the study group. The central canal volume values at the C1-C2 levels, ependymal cells, numbers of central canal surfaces, and Evans index values of the lateral ventricles were assessed and compared. Results: Choroid plexus edema and increased water vesicles were observed in animals with central canal dilatation. The Evans index of the brain ventricles was 0.33 ± 0.05, the mean volume of the central canal was 1.431 ± 0.043 mm3, and ependymal cells density was 5.420 ± 879/mm2 in the control group animals (n = 5); 0.35 ± 0.17, 1.190 ± 0.114 mm3, and 4.135 ± 612/mm2 in the SHAM group animals (n = 5); and 0.44 ± 0.68, 1.814 ± 0.139 mm3, and 2.512 ± 11/mm2 in the study group (n = 14). The relationship between the Evans index values, the central canal volumes, and degenerated ependymal cell densities was statistically significant (P < 0.05). Conclusions: This study showed that hydromyelia occurs following SAH-induced experimental hydrocephalus. Desquamation of ependymal cells and increased cerebrospinal fluid secretion may be responsible factors in the development of hydromyelia.

Investigation of the effects of berberine on bortezomib-induced sciatic nerve and spinal cord damage in rats through pathways involved in oxidative stress and neuro-inflammation.

Bortezomib (BTZ), a proteasome inhibitor, causes dose-limiting peripheral neuropathy in humans. Berberine (BBR), which has various biological and pharmacological properties, is known to have neuroprotective properties. The possible protective effects of BBR on peripheral neuropathy caused by BTZ were investigated in this study. For this purpose, BTZ was intraperitoneally given to Sprague dawley rats on the 1 st, 3rd, 5th, and 7th days with a cumulative dose of 0.8 mg/kg. Moreover, animals were orally administered 50 or 100 mg/kg BBR daily from day 1 to day 10. As a result of the analyzes performed on the sciatic nerve and spinal cord, it was observed that MDA levels and NRF-2, HO-1, NQO1, GCLC and GCLM mRNA transcript levels increased due to oxidative stress caused by BTZ, and the levels of these markers decreased after BBR administration. Also, it was determined that SOD, CAT, GPx and GSH levels increased after BBR treatment. It was observed that BTZ caused inflammation by triggering NF-κB, TNF-α, IL-1ß and IL-6 cytokines, on the other hand, with BBR treatment, these cytokines were suppressed and inflammation was alleviated. In addition, it was determined that the expressions of RAGE, STAT3, NLRP3 and TLR4, which have important roles in inflammation, increased with BTZ administration, but BBR suppressed the expressions of these genes. It was determined that the expressions of SIRT1, which plays an important role in neuropathic pain, and CREB-LI neurons, which has an active role in neurite outgrowth and survival, decreased with BTZ administration. It was observed that GFAP levels increased with BTZ administration and decreased with BBR administration. Given all the findings, it was concluded that BBR exhibits protective qualities in the sciatic nerve and spinal cord induced by BTZ.

Dry Mouth Caused by Facial Nerve Ischemia due to Subarachnoid Hemorrhage: An Experimental Study.

OBJECTIVE: Parasympathetic network damage results in facial nerve damage, sublingual ganglion degeneration, sublingual gland dysfunction, and dry mouth. In this study, subarachnoid hemorrhage (SAH) was considered to be the cause of dry mouth. METHODS: We assessed 23 hybrid rabbits, including 5 control (group 1, Control). One milliliter of serum saline was injected into the cisterna magna of 5 animals (group 2). SAH was induced by injecting 1 mL of autologous blood into the cisterna magna of 13 animals (group 3). The animals were killed after 3 weeks of induction. The animals' sublingual ganglion and sublingual gland were excised for histopathological examination. The number of degenerated cells in the sublingual ganglion, secretory vesicles, and secretory granules in the sublingual gland that contain salivary components were estimated using Sequential Window Acquisition of All Theoretical Mass Spectra data analysis. The values were compared by the Mann-Whitney U-test. RESULTS: The numbers of secretory vesicles in the sublingual gland were 5.3 ± 1.1 × 103 (group 1), 4.23 ± 0.45 × 103 (group 2), and 1.56 ± 0.22 × 103 (group 3); the numbers of secretory vesicles containing saliva in the sublingual gland were 324 ± 12.18 (group 1), 263 ± 36.23 (group 2), and 114 ± 23.14 (group 3); and the numbers of degenerated cells in the sublingual ganglion were 11 ± 3/mm3 (group 1), 98.43 ± 15.54/mm3 (group 2), and 346 ± 12.28/mm3 (group 3) (P < 0.05). CONCLUSIONS: Clinical findings in infection and diseases such as Sjögren syndrome, aseptic meningitis, and SAH are similar. However, until now, SAH has not been demonstrated experimentally to cause dry mouth. Discovering that SAH might cause dry mouth might prevent unnecessary use of antibiotics and decrease morbidity due to the wrong or late diagnosis.

Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats.

Docetaxel (DTX) is a chemotherapeutic agent used in the treatment of various malignancies but is often associated with central and peripheral neurotoxicity. The aim of this study was to investigate the neuroprotective effect of silymarin (SLM) against DTX-induced central and peripheral neurotoxicities in rats. Rats received 25 and 50 mg/kg body weight SLM orally for seven consecutive days after receiving a single injection of 30 mg/kg body weight DTX on the first day. SLM significantly decreased brain lipid peroxidation level and ameliorated brain glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in DTX-administered rats. SLM attenuated levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP) and activity of p38α mitogen-activated protein kinase (p38α MAPK) whereas caused an increase in levels of neural cell adhesion molecule (NCAM) in the brain and sciatic nerve of DTX-induced rats. In addition, SLM improved the histological structure of the brain and sciatic nerve tissues and decreased the expression of c-Jun N-terminal kinase (JNK) in the sciatic nerve whereas increased cyclic AMP response element binding protein (CREB) expression in the brain induced by DTX. Additionally, SLM markedly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and B-cell lymphoma-2 (Bcl-2) and downregulated the expression of Bcl-2 associated X protein (Bax) in the brain and sciatic nerve tissues of DTX-induced rats. Our results show that SLM can protect DTX-induced brain and sciatic nerve injuries by enhancing the antioxidant defense system and suppressing apoptosis and inflammation.

Protective Effects of Curcumin Against Paclitaxel-Induced Spinal Cord and Sciatic Nerve Injuries in Rats.

Paclitaxel (PTX) is an antineoplastic agent commonly used in the treatment of solid tumors and is known to cause dose-limiting peripheral neurotoxicity. This study was performed to evaluate the protective effect of curcumin (CUR) against PTX-induced spinal cord and sciatic nerve injuries in rats. The rats were administered PTX (2 mg/kg, BW) intraperitoneally for the first 5 consecutive days followed by administration of CUR (100 and 200 mg/kg, BW daily in corn oil) orally for 10 days. Our results showed that CUR significantly reduced mRNA expression levels of NF-κB, TNF-α, IL-6, iNOS and GFAP whereas caused an increase in levels of Nrf2, HO-1 and NQO1 in the spinal cord and sciatic nerve of PTX-induced rats. In addition, CUR suppressed the activation of apoptotic and autophagic pathways by increasing Bcl-2 and Bcl-xL, and decreasing p53, caspase-3, Apaf-1, LC3A, LC3B and beclin-1 mRNA expression levels. The results showed that CUR also maintained the spinal cord and sciatic nerve histological architecture and integrity by both LFB staining and H&E staining. Immunohistochemical expressions of 8-OHdG, caspase-3 and LC3B in the PTX-induced spinal cord tissue were decreased after administration of CUR. Taken together, our findings demonstrated that CUR has protective effects on PTX-induced spinal cord and sciatic nerve injuries in rats.

Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress, inflammation and apoptosis in rats.

Isoniazid (INH) is among the most important anti-tuberculosis agents widely prescribed. However, its clinical use is restricted due to its severe side effects associated with neurotoxicity. The aim of the present study was to investigate the neuroprotective effects of chrysin (CR), a natural antioxidant, against INH-induced neurotoxicity in rats. The rats were treated orally with INH (400 mg/kg body weight) alone or with CR (25 and 50 mg/kg body weight) for 7 consecutive days. INH administration significantly increased brain lipid peroxidation and resulted in a significant decrease in antioxidant biomarkers including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH). INH treatment also increased levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP) and activities of p38α mitogen-activated protein kinase (p38α MAPK) while decreasing levels of neural cell adhesion molecule (NCAM). Double immunofluorescence expressions of c-Jun N-terminal kinase (JNK) and Bcl-2 associated X protein (Bax) in brain tissues were increased after INH administration. Furthermore, INH increased mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase modifier subunit (Gclm), glutamate cysteine ligase catalytic subunit (Gclc), NF-κB, TNF-α, interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and GFAP in rat brain tissues. Co-treatment with CR increased anti-oxidant capacity as well as regulated inflammation and apoptosis in brain. Additionally, molecular docking results showed that CR had the potential to interact with the active sites of TNF-α and NFκ-B. In conclusion, CR improved INH-induced brain oxidative damage, inflammation and apoptosis, possibly through their antioxidant properties.

Quercetin provides protection against the peripheral nerve damage caused by vincristine in rats by suppressing caspase 3, NF-κB, ATF-6 pathways and activating Nrf2, Akt pathways.

In the present study, the protective effects of quercetin on peripheral neurotoxicity caused by vincristine, which is used effectively in the treatment of various types of cancers, were investigated by using different techniques. In the study, for 12 days, male Sprague Dawley rats were given 25 and 50 mg/kg doses of quercetin orally and were administered a 0.1 mg/kg dose of vincristine (a total cumulative dose of 1.2 mg/kg) intraperitoneally 30 min later. The protein levels of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase-1 (NQO1), glial fibrillary acidic protein (GFAP), and nuclear factor kappa B (NF-κB) were measured with ELISA; the immunopositivity of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and caspase 3 were determined with immunohistochemistry; the mRNA transcript levels of double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1), activating transcription factor-6 (ATF-6), glucose-regulated protein 78 (GRP78), Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), caspase 3, protein kinase B1/2 (Akt-1/2), and forkhead box transcription factor, class O1 (FOXO1) were determined with RT-PCR. The reduction of Nrf2 levels and HO-1 and NQO1 activities in the sciatic nerve tissue, the increase in the levels of 8-OHdG, and the increase in the levels of GFAP and NF-κB caused by vincristine was observed to cause oxidative stress, oxidative DNA damage, neuronal cell damage, and inflammation, respectively. Additionally, vincristine was determined to cause ER stress and apoptosis by increasing PERK, IRE1, ATF-6, and GRP78 and caspase 3 and Bax expressions and by decreasing Bcl-2 expressions. Vincristine causing Akt inhibition also shows that it prevents neuronal survival. However, quercetin was determined to relieve oxidative stress, oxidative DNA damage, neuronal cell damage, inflammation, ER stress, and apoptosis caused by vincristine and enable Akt activation. These results show that in rats, quercetin may have a protective effect against peripheral neurotoxicity caused by vincristine.

Lycopene protects against central and peripheral neuropathy by inhibiting oxaliplatin-induced ATF-6 pathway, apoptosis, inflammation and oxidative stress in brains and sciatic tissues of rats.

The fact that oxaliplatin (OXL), a platinum-based chemotherapeutic drug, causes severe neuropathy greatly limits its clinical use. This study investigated the effects of lycopene, a potent antioxidant, on OXL-induced central and peripheral neuropathy. In this study, 30 min after oral administration of LY at a dose of 2 mg/kg b.w./day and 4 mg/kg b.w./day on 1 st, 2nd, 4th and 5th days, rats were given 4 mg/kg b.w./day of OXL intraperitoneally. It was detected that LY decreased OXL-induced lipid peroxidation and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and the levels of glutathione (GSH) in brain tissue. LY showed anti-inflammatory effects by decreasing levels of mitogen-activated protein kinase-14 (MAPK14), nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) in brain and sciatic tissue. It was determined that OXL-induced endoplasmic reticulum stress (ERS) decreased because LY administration reduced the expressions of activating transcription factor-6 (ATF6), glucose-regulated protein-78 (GRP78), RNA-activated protein kinase (PKR)-like ER kinase and inositol-requiring enzyme-1 (IRE1). LY administration also reduced the damage of OXL-induced brain and sciatic tissue by increasing NCAM levels and decreasing GFAP levels. It was determined that caspase-3 immunopositivity markedly decreased by OXL and LY in combination. It was also observed that LY provided neuronal protection by increasing brain-derived neurotrophic factor (BDNF) levels, which decreased with OXL administration in sciatic tissue. The results demonstrate that LY can be beneficial in ameliorating OXL-induced central and peripheral nerve injuries by showing antioxidant, anti-inflammatory and anti-apoptotic properties in the brain and sciatic tissue.

Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions.

The purpose of the current study was to examine the neuroprotective effect of rutin against colistin-induced neurotoxicity in rats. Thirty-five male Sprague Dawley rats were randomly divided into 5 groups. The control group (orally received physiological saline), the rutin group (orally administered 100 mg/kg body weight), the colistin group (i.p. administered 15 mg/kg body weight), the Col + Rut 50 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 50 mg/kg body weight of rutin), the Col + Rut 100 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 100 mg/kg body weight of rutin). Administration of colistin increased levels of glial fibrillary acidic protein and brain-derived neurotrophic factor and acetylcholinesterase and butyrylcholinesterase activities while decreasing level of cyclic AMP response element binding protein and extracellular signal regulated kinases 1 and 2 (ERK1/2) expressions. Colistin increased oxidative impairments as evidenced by a decrease in level of nuclear factor erythroid 2-related factor 2 (Nrf-2), glutathione, superoxide dismutase, glutathione peroxidase and catalase activities, and increased malondialdehyde content. Colistin also increased the levels of the apoptotic and inflammatoric parameters such as cysteine aspartate specific protease-3 (caspase-3), p53, B-cell lymphoma-2 (Bcl-2), nuclear factor kappa B (NF-κB), Bcl-2 associated X protein (Bax), tumor necrosis factor-α (TNF-α) and neuronal nitric oxide synthase (nNOS). Rutin treatment restored the brain function by attenuating colistin-induced oxidative stress, apoptosis, inflammation, histopathological and immunohistochemical alteration suggesting that rutin supplementation mitigated colistin-induced neurotoxicity in male rats.

Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis.

Ifosfamide (IFA), a commonly used chemotherapeutic drug, has been frequently associated with encephalopathy and central nervous system toxicity. The present study aims to investigate whether morin could protect against acute IFA-induced neurotoxicity. Morin was administered to male rats once daily for 2 consecutive days at doses of 100 and 200 mg/kg body weight (BW) orally. IFA (500 mg/kg BW; i.p.) was administered on second day. The results showed that morin markedly inhibited the production of acetylcholinesterase (AChE), butrylcholinesterase (BChE), carbonic anhydrase (CA), glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and nuclear factor erythroid 2-related factor 2 (Nrf-2) induced by IFA. Morin ameliorated IFA-induced lipid peroxidation, glutathione (GSH) depletion, and decrease antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Histopathological changes and immunohistochemical expressions of c-Jun N-terminal kinase (JNK) and c-Fos in the IFA-induced brain tissues were decreased after administration of morin. Furthermore, morin was able to down regulate the levels of inflammatory and apoptotic markers such as nuclear factor kappa B (NF-κB), neuronal nitric oxide synthase (nNOS), tumor necrosis factor-α (TNF-α), p53, cysteine aspartate specific protease-3 (caspase-3) and B-cell lymphoma-2 (Bcl-2). Taken together, our results demonstrated that morin elicited a typical chemoprotective effect on IFA-induced acute neurotoxicity.