Biomedical subjects

Rao Muralikrishna Adibhatla

Publications and source records attributed to Rao Muralikrishna Adibhatla.

4 recordsLinked to original sources

PubMed2003

Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia.

Neuroprotection by citicoline (CDP-choline) in transient cerebral ischemia has been demonstrated previously. Citicoline has undergone several Phase III clinical trials for stroke, and is being evaluated for treatment of Alzheimer's and Parkinson's diseases. Phospholipid degradation and generation of reactive oxygen species (ROS) are major factors causing neuronal injury in CNS trauma and neurodegenerative diseases. Oxidative metabolism of arachidonic acid (released by the action of phospholipases) contributes to ROS generation. We examined the effect of citicoline on phospholipase A(2) (PLA(2)) activity in relation to the attenuation of hydroxyl radical (OH.) generation after transient forebrain ischemia of gerbil. PLA(2) activity (requires mM Ca(2+)) increased significantly (P < 0.05) in both membrane (50.2 +/- 2.2 pmol/min/mg protein compared to sham 35.9 +/- 3.2) and mitochondrial fractions (77.0 +/- 1.2 pmol/min/mg protein compared to sham 33.9 +/- 1.2) after cerebral ischemia and 2 hr reperfusion in gerbil, which was significantly attenuated (P < 0.01) by citicoline (membrane, 39.9. +/- 2.2 and mitochondria, 41.9 +/- 3.2 pmol/min/mg protein). In vitro, citicoline and its components cytidine and choline had no effect on PLA(2) activity, and thus citicoline as such is not a PLA(2) inhibitor. Ischemia/reperfusion resulted in significant OH. generation (P < 0.01) and citicoline significantly (P < 0.01) attenuated their formation (expressed as 2,3-dihydroxybenzoic acid/salicylate ratio; ischemia/24 hr reperfusion, 6.30 +/- 0.23; sham, 2.56 +/- 0.27; ischemia/24 hr reperfusion + citicoline, 4.85 +/- 0.35). These results suggest that citicoline affects PLA(2) stimulation and decreases OH. generation after transient cerebral ischemia.

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PubMed2002

Citicoline mechanisms and clinical efficacy in cerebral ischemia.

Citicoline, an intermediate in the biosynthesis of phosphatidylcholine (PtdCho), has shown beneficial effects in various CNS injury models and neurodegenerative diseases. PtdCho hydrolysis by phospholipase A(2) (PLA(2)) after cerebral ischemia and reperfusion yields arachidonic acid (ArAc) and lyso-PtdCho. ArAc oxidative metabolism results in formation of reactive oxygen species and lipid peroxides. Lyso-PtdCho could inhibit activity of cytidine triphosphate-phosphocholine cytidylyltransferase (the rate-limiting enzyme in PtdCho biosynthesis), resulting in impaired PtdCho synthesis. Citicoline significantly increased glutathione levels and attenuated release of ArAc and the loss of PtdCho, cardiolipin, and sphingomyelin following transient cerebral ischemia. These effects could be explained by an effect of citicoline on PLA(2). Based on these observations, a mechanism has been hypothesized. This Mini-Review summarizes recent experimental data on the effects of citicoline in cerebral ischemia and evaluates several factors that might have hindered efficacy of citicoline in stroke clinical trials in the United States. Clinical stroke trials of citicoline in Europe and Japan have demonstrated beneficial effects. U.S. trials shown only marginal effects, which might be due to the 24 hr time window, the dose and route of administration, and the stringency of the primary outcome parameters. Recent evaluation of U.S. clinical data suggests that reduction of infarct growth may be a more sensitive measure of the citicoline effect than improvement on the NIH Stroke Scale (NIHSS) by > or =7 points. The citicoline neuroprotective mechanism has not been clearly identified, and its potential in stroke treatment might still be fully recognized in the United States. The clinical efficacy of citicoline should be examined further in light of the recent phase III stroke clinical trials and experimental data for cerebral ischemia.

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PubMed2002

Polyamines and central nervous system injury: spermine and spermidine decrease following transient focal cerebral ischemia in spontaneously hypertensive rats.

Polyamines (putrescine, spermidine and spermine) are ubiquitous cellular components, but their specific role in central nervous system (CNS) injury has yet to be characterized. CNS injury results in increased activities of ornithine decarboxylase and spermidine/spermine-N(1)-acetyltransferase, and accumulation of putrescine. The present study determined the polyamine profile in three models of CNS injury, in two different species (gerbil and rat) and two strains of rats (Sprague-Dawley and spontaneously hypertensive): (1) transient focal cerebral ischemia in spontaneously hypertensive rats (SHR); (2) traumatic brain injury in Sprague-Dawley rats; and (3) transient forebrain ischemia in gerbils. While there was a significant increase in putrescine in all three models, spermine and spermidine levels were unaltered in forebrain ischemia and traumatic brain injury. However, transient focal cerebral ischemia shows depletion of spermine and spermidine levels in injured hemisphere compared to contralateral region. Exogenous spermine significantly restored the spermine as well as spermidine levels in the ipsilateral hemisphere after transient focal cerebral ischemia, but did not alter putrescine levels or the ratio of spermidine to spermine. The loss of spermine in particular, may have several consequences that contribute to ischemic injury, including destabilization of chromatin, decreased mitochondrial Ca(2+) buffering capacity, and increased susceptibility to oxidative stress. Based on our and other studies, we propose a tentative antioxidant mechanism of spermine neuroprotection.

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PubMed2002

Citicoline: neuroprotective mechanisms in cerebral ischemia.

Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine (PtdCho), has shown beneficial effects in a number of CNS injury models and pathological conditions of the brain. Citicoline improved the outcome in several phase-III clinical trials of stroke, but provided inconclusive results in recent clinical trials. The therapeutic action of citicoline is thought to be caused by stimulation of PtdCho synthesis in the injured brain, although the experimental evidence for this is limited. This review attempts to shed some light on the properties of citicoline that are responsible for its effectiveness. Our studies in transient cerebral ischemia suggest that citicoline might enhance reconstruction (synthesis) of PtdCho and sphingomyelin, but could act by inhibiting the destructive processes (activation of phospholipases). Citicoline neuroprotection may include: (i) preserving cardiolipin (an exclusive inner mitochondrial membrane component) and sphingomyelin; (ii) preserving the arachidonic acid content of PtdCho and phosphatidylethanolamine; (iii) partially restoring PtdCho levels; (iv) stimulating glutathione synthesis and glutathione reductase activity; (v) attenuating lipid peroxidation; and (vi) restoring Na(+)/K(+)-ATPase activity. These observed effects of citicoline could be explained by the attenuation of phospholipase A(2) activation. Based on these findings, a singular unifying mechanism has been hypothesized. Citicoline also provides choline for synthesis of neurotransmitter acetylcholine, stimulation of tyrosine hydroxylase activity and dopamine release.

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