[Effect of the adenosine A1 receptor agonist on demyelination and remyelination processes in lysolecithin induced demyelination in rat optic chiasm]

Demyelination in central nervous system is usually followed by remyelination; however, chronic lesions with subsequent functional impairment result from the eventual failure of remyelination process, as seen in multiple sclerosis. Remyelination is the process through which oligodendrocyte-progenitor cells [OPCs] restore new myelin sheathes around demyelinated axons. This study aimed to investigate the effect of A1 receptor agonist, N6-cyclohexyladenosine [CHA], on the demyelination and remyelination processes in rat optic chiasm following lysophosphatidylcholine [LPC]-induced demylination. In this experimental study, LPC was injected into the optic chiasm of three groups of rats [n=6]. Control group received aCSF on different days following LPC injection. Two groups of animals received CHA on days 0-14 or 14-28 post-lesion. Demyelination and remyelination levels were evaluated by recording visual evoked potential [VEP] from the scalp. The highest level of demyelination was occurred on day 7 post-lesion LPC injection and gradually reduced during the days 7-28. The P-wave latency was significantly increased on day 7 and then partially restored during the days 7-28 post-lesion. CHA administration during the days 0-14 attenuated demyelination process. In addition, CHA administration in remyelination phase [days 14-28] was able to potentiate the endogenous myelin repair. Injection of CHA could prevent the lysolecithin-induced variations in VEP. The effects of CHA may be mediated through increment of OPCs proliferation and their differentiation into myelinating oligodendrocytes

[PKC mediates endogenous inhibition of myelin repair in the context of local demyelination induced in mice optic chiasm]

Axon regeneration in adult CNS is limited by the presence of inhibitory proteins associated with myelin. Although blocking PKC activity attenuates the ability of CNS myelin to inhibit neurite outgrowth, the role as well as mechanisms underlying the remyelination inhibition in CNS are still largely unknown. Considering the role of PKC in axonal regeneration and the vulnerability of optic chiasm in multiple sclerosis [MS], we assessed the effect of PKC inhibition on remyelination of lysolecithin induced demyelinated optic chiasm. Demyelination was induced by stereotaxic intra-chiasmatic injection of 1 micro l lysolecithin [%1] in male mice. Intracerebroventricular daily injection of a PKC inhibitor [GO6976] was done for 14 days post-lesion. Demyelination and remyelination patterns in optic chiasm were confirmed through histological verification and electrophysiological study using Luxol fast blue staining and visual evoked potentials [VEP] recording, respectively. In lysolecithin treated animals, demyelination was mostly marked at days 3 and 7 post-lesion and an incomplete remyelination occurred at day 14 post-lesion. VEP recording showed increased P-latency at the days 3 and 7 post-lesion while it partially decreased at day 14. Following the inhibition of PKC, while the extent of demyelination and P-latency slightly decreased at the days 3 and 7 post-lesion, it recovered at day 14. VEP recording data were confirmed by histological verification. Inhibition of PKC activity could represent a potential therapeutic approach for stimulating the remyelination process in the context of multiple sclerosis

Effect of low-frequency stimulation on adenosine A[1] and A[2A] receptors gene expression in dentate gyrus of perforant path kindled rats

It has been suggested that low frequency stimulation [LFS] exerts its inhibitory effect on epileptogenesis through adenosine receptors activation. In the present study, effect of different LFS frequencies on A1 and A2A receptors gene expression was investigated in perforant path kindled seizures. Animals were kindled by perforant path stimulation. Afterdischarges were recorded from the dentate gyrus. LFS [0.5, 1 and 5 Hz] was applied at the end of each kindling stimulation. On the 7th day, A1 and A2A receptors gene expression were evaluated in the dentate gyrus. Application of different LFS frequencies retarded the kindling acquisition. Also, it decreased the afterdischarge durations and behavioural seizure stages 4 and 5 significantly. LFS application prevented the kindling induced decrease in the A1 receptor gene expression. On the other hand, LFS attenuated the level of A2A receptor gene expression in the dentate gyrus. LFS had the most effect at the frequency of 5 Hz. It may be suggested that antiepileptogenic effects of LFS is mediated somehow through changes in the gene expression of adenosine A1 [which has inhibitory effects] and A2A [which has excitatory effects] receptors. These effects might be somehow frequency dependent

role of adenosine A1 receptor activity of piriform cortex neurons on amygdala kindled seizures in rats

Considering the anticonvulsant effects of A1 Adenosine Receptors and the anatomical connections between piriform Cortex and Amygdala, in this study, the role of A1 adenosine receptors activity of piriform cortex neurons on amygdala kindled seizures was investigated in rats. The rats were fully kindled by daily electrical stimulation of amygdala. N6-cyclohexyleadenosine [CHA; 1,10 and 100 mM], as a selective A1 agonist and 1,3-dimethyl-8-cyclohexylexantine [CPT; 20 and 10 mM], as a selective A1 antagonist were microinjected [0.5ml, 0.25 ml/min] into the piriform cortex. Animals were stimulated at 5, 15 or 90 min after drug microinjection and seizure parameters were measured. Intra-piriform CHA [10 or 100 mM] reduced afterdischarge duration and stage 5 seizure duration and prolonged stage 4 latency significantly. Pretreatment with CPT [10 mM] 5 min before CHA [100 mM] eliminated the effects of CHA. These observations suggest that A1 adenosine receptors activity in piriform cortex reduced the seizure severity and attenuated the distribution of seizure activity to other brain regions

Adenosine Al receptors of amygdala has not anticonvulsant effects on piriform cortex kindled seizures in rats

Adenosine is an endogenous anticonvulsant which exerts its anticonvulsant effects through adenosine Al receptors. As the piriform/amygdala is a critical circuit for limbic seizure propagation, in this study the role of amygdala Al receptors on piriform cortex kindled seizures was investigated. Rats were kindled by daily electrical stimulation of piriform cortex. In the first experiment fully kindled animals received intra-amygdala N6-cyclohexyladenosine [CHA; 10-500 micro M, a selective Al receptor] or 2% lidocaine [for reversal neuronal inhibition] bilaterally. 5 min later, animals were stimulated and seizure parameters were measured. In the second experiment, the effect of daily microinjection of CHA [100 microM] into the amygdala on piriform cortex kindling rate was investigated. Different doses of CHA had no effect on kindled seizure parameters. On the other hand, intra-amygdala 2% lidocaine reduced the kindled seizures severity. There were significant increase in stage 4 latency and decrease in stage 5 duration. Also, daily intra-amygdala CHA had no significant effect on kindling rate. The amygdala neuronal activity has a role in propagation of epileptic seizures from piriform cortex. Elimination of this activity by lidocaine decreases the severity of piriform cortex kindled seizures. However, the amygdala Al receptors have no role in this regard