Maryam Khaleghi Ghadiri

History of headache in medieval Persian medicine

Despite the many studies into the history of headache, the ways in which the disorder was treated in medieval Persia are not well known in the west. Several documents still exist from which the definitions and treatments of headache in medieval Persia can be ascertained. These documents give detailed and precise clinical information on different types of headache. The medieval doctors listed various signs and symptoms, apparent causes, and hygienic and dietary rules for prevention of headaches. The medieval writings are both accurate and vivid, and they provide long lists of substances used in the treatment of headaches. Many of the approaches of physicians in medieval Persia are accepted today; however, still more of them could be of use to modern medicine. The main objective of this paper is to review the clinical approaches to headache used by practitioners in medieval Persia.

Lavender and the Nervous System

Lavender is traditionally alleged to have a variety of therapeutic and curative properties, ranging from inducing relaxation to treating parasitic infections, burns, insect bites, and spasm. There is growing evidence suggesting that lavender oil may be an effective medicament in treatment of several neurological disorders. Several animal and human investigations suggest anxiolytic, mood stabilizer, sedative, analgesic, and anticonvulsive and neuroprotective properties for lavender. These studies raised the possibility of revival of lavender therapeutic efficacy in neurological disorders. In this paper, a survey on current experimental and clinical state of knowledge about the effect of lavender on the nervous system is given.

Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues

There is unequivocal electrophysiological evidence that spreading depression (SD) can trigger epileptiform field potentials. In vitro experiments on human brain tissues indicated that γ-aminobutyric acid (GABA)-mediated inhibition prevented this process. Intra- and extracellular recordings of bioelectrical activities were performed in the rodent neocortex, hippocampus and amygdala after perfusion of low concentrations of the GABAA antagonist bicuculline and induction of SD by KCl application. Induction of SD in combined amygdala-hippocampus-cortex slices pre-treated with low concentration of bicuculline triggered epileptiform burst discharges in cortical as well as subcortical brain structures. Propagation of SD significantly depolarized the membrane, decreased the amplitude and duration of action potentials (APs) and after-hyperpolarization as well as the neuronal membrane input resistance and the amplitude of threshold potentials. Ten to twenty minutes after induction of SD, the pattern of APs changed from regular firing to a series of APs riding on an underlying paroxysmal depolarization shift before the appearance of typical ictaform activities. Changes of characteristic features of APs occurred after SD persisted during the appearance of epileptiform activities. These results indicate that SD increases neuronal excitability and facilitates synchronization of neuronal discharges in the presence of partial disinhibition of neuronal tissues. Our findings might explain the occurrence of seizures in neurological disorders with partial impairment of inhibitory tone, such as brain ischemia and epilepsy.

Sequential changes in neuronal activity in single neocortical neurons after spreading depression

Background: Cortical spreading depression (CSD) has an important role in migraine with aura. Prolonged neuronal depression is followed by a late excitatory synaptic plasticity after CSD. Method: Intra- and extracellular recordings were performed to investigate the effect of CSD on intracellular properties of mouse neocortical tissues in the late excitatory period. Results: During CSD, changes in the membrane potentials usually began with a relatively short hyperpolarization followed by an abrupt depolarization. These changes occurred roughly at the same time point after CSD as the beginning of the negative extracellular deflection. Forty-five minutes after CSD, neurons showed significantly smaller amplitude of afterhyperpolarization and a reduced input resistance. Depolarization and hyperpolarization of the cells by constant intracellular current injections in this period significantly changed the frequency of the action potentials. Conclusion: These data indicate higher excitability of the neocortical neurons after CSD, which can be assumed to contribute to hyperexcitability of neocortical tissues in patients suffering from migraine.

The effects of tetanic stimulation on plasticity of remote synapses in the hippocampus-perirhinal cortex-amygdala network

In the temporal lobe, multiple synaptic pathways reciprocally link different structures. These multiple pathways play an important role in the integrity of the function of the temporal lobe and malfunction in this network has been suggested to underlie some neurological disorders such as epilepsy. To test whether the induction of long‐term potentiation (LTP) in one temporal lobe structure would modulate functional synaptic plasticity in other structures of this network, tetanic stimulation was applied to the white matter of the perirhinal cortex, Schaffer collaterals of the hippocampus, or the external capsule in combined rat amygdala–hippocampus–cortex slices. This tetanic stimulation was accompanied by enhancement of the evoked field potential slope in the third layer of perirhinal cortex, hippocampal CA1 area, and the lateral amygdala. Induction of LTP in each of these structures was concomitant with increased evoked field potentials in the neighboring structures. Surgical disconnection of anatomical pathways between these structures inhibited this concomitant enhancement of theevoked field potential slope. Both NMDA and AMPA glutamate sub‐receptors were involved in changes of synaptic plasticity elicited by induction of LTP in the neighboring structures. The present data indicate a reciprocal control among the perirhinal cortex, the amygdala, and the hippocampus plasticity. This could be important for the formation and retention of the medial temporal lobe‐dependent memory and may play a role in the involvement of all different regions of the temporal lobe in pathological conditions such as epilepsy that affect this brain structure. Synapse 66:965–974, 2012.

Immunomodulatory Effect of Toll-Like Receptor-3 Ligand Poly I:C on Cortical Spreading Depression.

The release of inflammatory mediators following cortical spreading depression (CSD) is suggested to play a role in pathophysiology of CSD-related neurological disorders. Toll-like receptors (TLR) are master regulators of innate immune function and involved in the activation of inflammatory responses in the brain. TLR3 agonist poly I:C exerts anti-inflammatory effect and prevents cell injury in the brain. The aim of the present study was to examine the effect of systemic administration of poly I:C on the release of cytokines (TNF-α, IFN-γ, IL-4, TGF-β1, and GM-CSF) in the brain and spleen, splenic lymphocyte proliferation, expression of GAD65, GABAAα, GABAAβ as well as Hsp70, and production of dark neurons after induction of repetitive CSD in juvenile rats. Poly I:C significantly attenuated CSD-induced production of TNF-α and IFN-γ in the brain as well as TNF-α and IL-4 in the spleen. Poly I:C did not affect enhancement of splenic lymphocyte proliferation after CSD. Administration of poly I:C increased expression of GABAAα, GABAAβ as well as Hsp70 and decreased expression of GAD65 in the entorhinal cortex compared to CSD-treated tissues. In addition, poly I:C significantly prevented production of CSD-induced dark neurons. The data indicate neuroprotective and anti-inflammatory effects of TLR3 activation on CSD-induced neuroinflammation. Targeting TLR3 may provide a novel strategy for developing new treatments for CSD-related neurological disorders.

Periodic fasting alters neuronal excitability in rat neocortical and hippocampal tissues.

Dietary restriction has been shown to be associated with marked changes in brain function. Periodic fasting was suggested to be beneficial in reducing both the incidence and severity of some neurological disorders. The aim of this investigation was to study the effect of periodic fasting on the neuronal network excitability in the neocortex and hippocampus and its possible influence on the brain under pathological conditions. Direct current (DC) recordings in the somatosensory neocortex of fasting rats (15 h water and food deprivation per day) during drinking revealed a negative potential shift. Using voltage sensitive dye imaging and tetanus-induced long-term potentiation (LTP) in ex vivo/in vitro experiments, neuronal network activities as well as synaptic efficacy were investigated in rat neocortical and hippocampal slices after 4 weeks of periodic fasting. Stimulus-induced patterns of bioelectric activity showed enhanced neuronal network excitability in the neocortex and decreased bioelectric activity in the hippocampus. LTP was significantly increased in neocortical slices and inhibited in hippocampal tissues. Both hippocampal and neocortical tissues exhibited a higher tolerance to hypoxic stress but not to 0-Mg(2+)-eliciting epileptiform field potentials. Neocortical slices also exhibited a higher threshold for the initiation of spreading depression. These experiments indicate that repetitive DC potential shifts occurring in fasting rats change the pattern of bioelectrical activities in cortical and subcortical regions. Through these alterations, the neocortex and hippocampus may become tuned for the efficient regulation of consummatory behaviour.

Astrocyte-mediated inflammation in cortical spreading depression:

Background Cortical spreading depression (CSD) related diseases such as migraine, cerebrovascular diseases, and epilepsy have been associated with reactive astrocytosis, yet the mechanisms of these tissue changes remain unclear. CSD-induced inflammatory response has been proposed to play a role in some neurological disorders and thus may also contribute to reactive astrocytosis. Methods Using ex vivo brain slices and in vitro astrocytic cultures, we aimed to characterize CSD related changes in astrocytes and markers of inflammation by immunocyto- and immunohistochemistry. CSD was induced by application of KCl (3 mol/l) on neocortical tissues. The application of KCl was repeated weekly over the course of four weeks. Results CSD induced an increase in the mean number and volume of astrocytes in rat brain tissue when compared to controls, whereas no changes in neuronal numbers and volumes were seen. These cell-type specific changes, suggestive of reactive astrocytosis, were paralleled by an increased expression of protein markers indicative of astrocytes and neuroinflammation in ex vivo brain slices of animals undergoing CSD when compared to sham-treated controls. Cultured astrocytes showed an increased expression of the immune modulatory enzyme indoleamine 2,3-dioxygenase and an elevated expression of the pro-inflammatory markers, IL-6, IL-1β, and TNFα in addition to increased levels of toll like receptors (TLR3 and TLR4) and astrocytic markers after induction of CSD. Conclusion These findings indicate that CSD related reactive astrocytosis is linked to an upregulation of inflammatory markers. Targeting inflammation with already approved and available immunomodulatory treatments may thus represent a strategy to combat or ameliorate CSD-related disease.

Gabapentin prevents cortical spreading depolarization-induced disinhibition

Cortical spreading depolarization (CSD) has an important role in brain diseases such as stroke, subarachnoid hemorrhage, migraine with aura, and epilepsy. Several anti-epileptic drugs (AEDs) are used to treat paroxysmal brain diseases and are thus known to suppress CSD. One of these AEDs is gabapentin (GBP) which has been traditionally used for treatment of some CSD-related neurological diseases. We applied intra- and extracellular recordings to investigate the effect of CSD on inhibitory post synaptic potentials (IPSPs) and synaptic properties of rodent neocortex after application of GBP. Application of GBP after CSD increased the amplitude of IPSPs. In addition, GBP inhibited induction of long-term potentiation after CSD. These data support an effect of GBP on GABA-mediated inhibition in the late hyperexcitable phase of CSD. Modulations of synaptic properties and post-CSD GABAergic function are likely GBPs mechanisms of action in CSD-related disorders. These mechanisms could be targeted for further drug discovery in CSD-related diseases.

Apoptosis Following Cortical Spreading Depression in Juvenile Rats

Repetitive cortical spreading depression (CSD) can lead to cell death in immature brain tissue. Caspases are involved in neuronal cell death in several CSD-related neurological disorders, such as stroke and epilepsy. Yet, whether repetitive CSD itself can induce caspase activation in adult or juvenile tissue remains unknown. Inducing repetitive CSD in somatosensory cortices of juvenile and adult rats in vivo, we thus aimed to investigate the effect of repetitive CSD on the expression caspase-3, caspase-8, caspase-9, and caspase-12 in different brain regions using immunohistochemistry and western blotting techniques. Higher numbers of dark neurons and TUNEL-positive cells were observed in the hippocampal CA1 and CA3 regions as well as in the entorhinal and somatosensory cortices after CSD in juvenile rats. This was accompanied by higher expressions of caspase-3, caspase-8, and caspase-9. Caspase-12 levels remained unchanged after CSD, suggesting that endoplasmic reticulum stress is not involved in CSD-triggered apoptosis. Changes in caspase expression were paralleled by a decrease of procaspase-3, procaspase-8, and procaspase-9 in juvenile rat brain tissue subjected to CSD. In contrast, repetitive CSD in adult rats did not result in the upregulation of caspase signaling. Our data points to a maturation-dependent vulnerability of brain tissue to repetitive CSD with a higher degree of apoptotic damage and caspase upregulation observed in juvenile tissue. Findings suggest a key role of caspase signaling in CSD-induced cell death in the immature brain. This implies that anti-apoptotic treatment may prevent CSD-related functional deficits in the immature brain.