Neuro-modulatory impact of felodipine against experimentally-induced Parkinson's disease: Possible contribution of PINK1-Parkin mitophagy pathway.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, characterized by motor and psychological dysfunction. Palliative treatment and dopamine replenishment therapy are the only available therapeutic options. Calcium channel blockers (CCBs) have been reported to protect against several neurodegenerative disorders. The current study was designed to evaluate the neuroprotective impact of Felodipine (10 mg/kg, orally) as a CCB on motor and biochemical dysfunction associated with experimentally induced PD using rotenone (2.5 mg/kg, IP) and to investigate the underlying mechanisms. Rotenone induced deleterious neuromotor outcomes, typical of those associated with PD. The striatum revealed increased oxidative burden and NO levels with decreased antioxidant capacity. Nrf2 content significantly decreased with the accumulation of α-synuclein and tau proteins in both the substantia nigra and striatum. These observations significantly improved with felodipine treatment. Of note, felodipine increased dopamine levels in the substantia nigra and striatum as confirmed by the suppression of inflammation and the significant reduction in striatal NF-κB and TNF-α contents. Moreover, felodipine enhanced mitophagy, as confirmed by a significant increase in mitochondrial Parkin and suppression of LC3a/b and SQSTM1/p62. In conclusion, felodipine restored dopamine synthesis, attenuated oxidative stress, inflammation, and mitochondrial dysfunction, and improved the mitophagy process resulting in improved PD-associated motor impairment.

Crocin reverses unilateral renal ischemia reperfusion injury-induced augmentation of oxidative stress and toll like receptor-4 activity.

Renal Ischemia (RI) usually develops as a secondary manifestation of hypertension, various cardiovascular disorders and renal transplantation. It exerts hypoxic oxidative stress to kidneys, together with stimulation of several immune-mediated inflammatory cascades. Such events eventually damage renal tubules and glomeruli, driving acute kidney injury (AKI) and ultimately, renal failure. Crocin; the main bioactive constituent of Crocus sativus extract has been reported to demonstrate numerous pharmacological merits. In the current study, unilateral renal ischemia reperfusion injury (URIRI) was induced in rats by unilateral clamping of the left renal pedicle for 45 min followed by 24 h of reperfusion. Daily pre-treatment with crocin (20 mg/kg, orally) for 7 days, significantly improved all signs of renal injury. Biochemically, kidney functions; including serum creatinine (Sr Cr), blood urea nitrogen (BUN), proteinuria and creatinine clearance (Cr Cl) significantly improved. Inflammatory biomarkers; serum lactate dehydrogenase (LDH) and kidney nitric oxide (Nos) contents significantly declined. Oxidant/antioxidant balance was significantly restored; manifested in recovery of renal superoxide dismutase (SOD) activity, glutathione (GSH) concentration, malondialdehyde (MDA) content and restoration of serum catalase activity. Kidney contents of inflammatory cytokine interleukin-6 (IL6) and toll-like receptors 4 (TLR4) significantly declined as well. Histopathologically, crocin pretreatment resulted in signs of improvement with minimal renal lesions with significant decrease in renal inflammatory cells count. In conclusion, crocin induced restoration of normal kidney functions is mediated through multiple mechanisms including mainly attenuation of oxidative stress and inflammation via down-regulation of renal TLR4 and IL6 expression.

Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats.

Diabetic Nephropathy (DN) is one of the main complications associated with diabetes mellitus. Persistently elevated blood glucose level drives histopathological changes in renal tissues that hinder normal kidney functions. In the current study, crocin; the main bioactive constituent of Crocus sativus was investigated as a reno-protective agent against DN by virtue of its numerous pharmacological activities. Diabetes was induced in male Sprague-Dawely rats through intravenous injection of streptozocin (STZ) (50 mg/kg), DN was confirmed eight weeks post diabetes induction. Daily oral crocin for eight weeks (20 mg/kg) significantly reduced blood glucose level with a significant increase in insulin level. Moreover, crocin improved impaired kidney functions as manifested in reduction of serum creatinine levels, blood urea nitrogen and proteinuria with concomitant increase in urinary creatinine clearance. Furthermore, biomarkers of cell injury and tissue necrosis like LDH activity was significantly reduced, kidney content of NOS significantly declined likewise. In addition, renal antioxidants such as SOD, GSH and serum catalase activity significantly increased with concomitant reduction of kidney MDA; biomarker of oxidative load. Kidney content of toll-like receptors 4 and IL-6 significantly declined with simultaneous suppression of nuclear factor kappa-B (NF-κB/p65) protein expression and immuno-staining in rat renal cortex. Furthermore, crocin inhibited progression of renal fibrosis as seen with reduction of renal hydroxyproline and collagen content, TGF-ß immuno-staining and Masson's Trichrome positive tissue. Histopathologically, crocin pretreatment was associated with minimal renal damage with fewer fibrotic lesions. There was a concomitant restoration of renal tubules integrity with preservation of glomerular space area. In conclusion, crocin's ameliorative impact on DN may be attributed to its free radicals scavenging properties, its ability to enhance host antioxidant defense system and its ability to inhibit inflammatory and fibrotic cascades activation.