Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia?

Background and Purpose— Stroke is a leading cause of disability and death in the United States, yet limited therapeutic options exist. The need for novel neuroprotective agents has spurred efforts ...

The Role of Protein Kinase C in Cerebral Ischemic and Reperfusion Injury

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(15)00084-5.pdf

The multi-tasked life of GM1 ganglioside, a true factotum of nature

Protective effect of melatonin against hippocampal DNA damage induced by intraperitoneal administration of kainate to rats.

The cytosolic antioxidant, copper/zinc superoxide dismutase, attenuates blood-brain barrier disruption and oxidative cellular injury after photothrombotic cortical ischemia in mice.

A vascular thrombotic lesion localized to the rat sensorimotor cortex was produced following intravenous injection of the photosensitive dye rose bengal, and its activation with a small beam of high-intensity white light focused to the skull overlaying the sensorimotor cortex In the sensorimotor cortex at various times after the triggering event, two contiguous brain regions with different degree(s) of neuronal damage can be distinguished: (1) a primary thrombotic ischemic core where the majority of cells are dead and (2) a penumbra region surrounding the core lesion in which a slower progressive neuronal degeneration is occurring Importantly, in both brain regions the neuronal degeneration is associated with the activation and persistent translocation of protein kinase C (PKC) as indicated by an increase in 4-beta-3H-phorbol-12,13-dibutyrate (3H-PDBu) binding Moreover, the demonstration that in the area penumbra the neuronal degeneration and the persistent translocation of PKC can be inhibited by a pretreatment with dizocilpine (ie, MK-801) indicates that the dynamics of the progression of the neuronal degeneration are maintained by glutamate accumulating in the extraneuronal fluids MK-801 additionally prevents the transcriptional activation of several immediate-early genes (IEGs) (eg, c-fos) and their cognate third nuclear messenger (ie, c-Fos) expression present in the hemisphere ipsilateral to the lesion On the other hand, LIGA4 and LIGA20 derivatives of GM1 lysoganglioside reduce the membrane translocation of PKC and the neuronal damage in the penumbra area, but fail to change the increase of IEG expression in the cortex ipsilateral to the lesion

https://www.jneurosci.org/content/jneuro/13/6/2483.full.pdf

Semisynthetic sphingolipids prevent protein kinase C translocation and neuronal damage in the perifocal area following a photochemically induced thrombotic brain cortical lesion

In culture the protracted and abusive stimulation of glutamate (GLU) receptors results in neuronal death through a mechanism involving the persistent translocation of PKC and the destabilization of (Ca2+)i homeostasis [(Ca2+)i HD]. In contrast, intermittent GLU receptor use elicits a coordinated expression of immediate early genes (IEG) acting as nuclear third messenger. Brain ischemia also is known to result in the paroxysmal abusive stimulation of glutamate receptors. The glutamate receptive elements in turn degenerate largely as a function of their inability to control homeostatic Ca2+ due to the irreversible translocation of PKC. In the present study we employed an in vivo model of focal brain ischemia using the photosensitive dye, Rose bengal. With this model we sought to determine the neuroprotective actions of MK-801, a noncompetitive blocker of GLU at the NMDA-sensitive receptor and of the semisynthetic gangliosides LIGA 4 and LIGA 20 which in vitro have been demonstrated to block PKC translocation. Moreover, we sought to establish whether the persistent stimulation of ionotropic glutamate receptors would led to a change in ionotropic glutamate expression in the focal and perifocal area. Importantly, the perifocal area (i. e., the region surrounding the area of primary insult) is a region in which profound cellular reorganization occurs including neuronal death and glial proliferation and is a key region to target various neuroprotective drugs aimed at ameliorating the neurodegeneration following stroke. Receptor abuse dependent antagonists (RADA) drugs such as gangliosides selectively curtail the amplification steps that specifically differentiate signal transduction following physiological receptor use from that following pathological receptor abuse.(ABSTRACT TRUNCATED AT 250 WORDS)

R. Hayes

Papers

Semisynthetic sphingolipids prevent protein kinase C translocation and neuronal damage in the perifocal area following a photochemically induced thrombotic brain cortical lesion

Sequelae of biochemical events following photochemical injury of rat sensory-motor cortex: mechanism of ganglioside protection.