Regulation Of Astrocytic Glutamate Metabolism By Histamine And H1Receptors

In the mammalian CNS, glutamate is the major excitatory neurotransmitter. Extracellular glutamate levels are maintained at relatively low levels to ensure an appropriate signal-to-noise ratio and to prevent excessive activation of glutamate receptors that can result in neuronal death. The latter phenomenon is known as ’excitotoxicity’and has been associated with a wide range of neurological disease such as epilepsy and brain ischemia. Unfortunately, clinical trials with glutamate receptor antagonists that would logically seem to prevent the effects of excessive receptor activation have been associated with little clinical benefit or untoward side effects. Therefore, it is necessary to find new therapeutic targets which do not impair the physiological function of glutamate. Accumulating evidences support that glia cells especially astrocytes play an important role in glutamate metabolism and homeostasis. Following synaptic release, glutamate is mainly taken up by the astrocytic glutamate transporter GLT-1or GLAST, and then converted into glutamine by glutamine synthetase (GS). Subsequently, the glutamine in astrocytes is transported back to the presynaptic terminals and converted to glutamate or GABA for reuse. This process is named glutamate-glutamine cycle. Interfering the glutamate-glutamine cycle or it’s key components such as glutamate transporter and GS have been reported to influence the glutamate levels and glutamate-induced excitotoxicity. Therefore, the key components of astrocytic glutamate metabolism pathway may be potential therapeutic targets for excitotoxicity and relative neurological disease.Histamine is recognized as an important neurotransmitter or neuromodulator in the CNS. Histaminergic neurons are located in the hypothalamus tuberomammillary (TM) nucleus, and project widely throughout the brain. Four histamine receptors have been identified (H1-H4), and three of them (H1-H3) are prominently expressed in the brain. Previous works suggest that central histamine via its receptors may be an endogenous protective factor for neurological disease such as epilepsy and brain ischemia. However, the mechanisms underlying this neuroprotection are largely unclear.Our previous works implicate that histamine also interferes glutamate levels in the brain. Dose histamine protect against excitotoxicity and relative neurological disease by modulating the key components of astrocytic glutamate metabolism pathway? In the present study, we first confirmed the effects of H1-antagonists which are among the most widely used medications on seizure susceptibility after drug withdrawal. Then we examined whether the increased seizure susceptibility was resulted from impairing glutamine synthetase. Based on the above results, we also investigated whether histamine regulates the astrocytic glutamate transporter GLT-1, and thereby exerts neuronal protection against excitotoxicity.1chronic Hl-antagonist treatment increases seizure susceptibility after withdrawal by impairing glutamine synthetaseChronic treatment with H1-antagonist diphenhydramine or pyrilamine lowered the afterdischarge threshold and promoted the progression of amygdaloid kindling seizures10days after drug withdrawal in rats. Seizure susceptibility enhancement was also observed in pentylenetetrazol model one day, five days and ten days after drug withdrawal from a two-week treatment with diphenhydramine. Meanwhile, GS activity and expression in the cortex or hippocampus decreased simultaneously with a marked decline of glutamine and GABA content. Comparably inhibiting glutamine synthetase activity by methionine sulfoximine (MSO) was also sufficient to increase susceptibility, while supplement with glutamine reversed the high susceptibility10days after diphenhydramine withdrawal. Moreover, the seizure susceptibility increased10days after diphenhydramine withdrawal in wild-type mice but not in histidine decarboxylase knockout mice, which lack histamine. In cultured astrocytes, diphenhydramine and pyrilamine also decreased the expression of GS, which did not recover immediately after drug withdrawal, but was reversed by prior addition of histamine or the H1agonist histamine trifluoromethyl toluidide (HTMT). Therefore, the present studies indicated that chronic H1-antagonist treatment produces long-lastingly increase in seizure susceptibility in nonepileptic rodents after drug withdrawal and its mechanism involves impairment of astrocytic glutamine synthetase through blocking H1receptors.2Histamine up-regulates astrocytic glutamate transporter1and protects neurons against ischemic injuryIn acute hippocampal slices, histamine selectively increased GLT-1expression independent of neuronal activities. Similar up-regulation of GLT-1was also observed after histamine treatment in pure cultured astrocytes, which was abolished by H1receptor antagonist or PKC inhibitor. Cell surface biotinylation and whole-cell patch recordings of glutamate transporter current confirmed the up-regulation of functional GLT-1following histamine exposure. Histamine treatment decreased the extracellular glutamate content and alleviated neuronal cell death induced by exogenous glutamate challenge. Moreover, we found a significant neuroprotective effect of histamine in brain slices after oxygen-glucose deprivation (OGD). In addition, histidine, the precursor of histamine, also showed neuroprotection against ischemic injury, which was accompanied by reversion of declined expression of GLT-1in adult rats subjected to middle cerebral artery occlusion (MCAO). These neuroprotective effects of histamine were abolished by GLT-1specific inhibitor dihydrokainate or H1receptor antagonist.In conclusion, we found that chronic treatment with HI-antagonists increased seizure susceptibility in nonepileptic rodents, and this effect lasted for a long time after drug withdrawal. The mechanism involved impairment of astrocytic GS expression or activity through blocking histamine H1receptors. It suggests that caution may be exercised by those who have chronically taken H1-antagonists, especially who are at high risk of epileptogenesis. On the other hand, histamine up-regulates astrocytic glutamate transporter GLT-1via H1receptor in both acute brain slices and cultured astrocytes, leading to reduction of extracellular glutamate content and neuroprotection against excitotoxicity and ischemic injury. These results reveal a new endogenous regulator of GLT-1and uncover a novel mechanism underlying histamine-induced neuroprotection against excitotoxic injury.