Neuroactive Substances Research Articles

The effects of the Brazilian ant Dinoponera quadriceps venom on chemically induced seizure models

Arthropod venoms are potential sources of neuroactive substances, providing new tools for the design of drugs. The aim of this study was to evaluate the effects of Dinoponera quadriceps venom (DqV) on seizure models in mice induced by pentylenetetrazole (PTZ), pilocarpine, and strychnine. In the PTZ model, intraperitoneal treatment with DqV (0.5mg/kg) increased the time until the first seizure and the percentage of survival (155.4±27.7s/12.5%, p<0.05) compared to the control group (79.75±3.97s/0%), whereas endovenous treatment (0.1 and 0.5mg/kg) decreased the time until the first seizure (0.1mg/kg: 77.83±5.3s versus 101.0±3.3s in the control group; 0.5mg/kg: 74.43±3.9s versus 101.0±3.3s for the control group, p<0.05). We did not observe significant changes in the pilocarpine- and strychnine-induced seizure models. In assays that measured oxidative parameters in the PTZ model, intraperitoneal treatment with DqV (0.5 and 2.0mg/kg) only decreased the levels of MDA and nitrite in the cortex. However, endovenous treatment with DqV (0.1 and 0.5mg/kg) increased the levels of MDA in the cortex and hippocampus and at a dose of 0.5mg/kg in the striatum. Moreover, increased in nitrite content was observed in all three of the brain regions analyzed. Taken together, the D. quadriceps venom caused both neuroprotective and neurotoxic effects in a PTZ-induced seizure model, and this effect was dependent on the route of administration used.

Differential responses to ω-agatoxin IVA in murine frontal cortex and spinal cord derived neuronal networks

ω-Agatoxin-IVA is a well known P/Q-type Ca2+ channel blocker and has been shown to affect presynaptic Ca2+ currents as well postsynaptic potentials. P/Q-type voltage gated Ca2+ channels play a vital role in presynaptic neurotransmitter release and thus play a role in action potential generation. Monitoring spontaneous activity of neuronal networks on microelectrode arrays (MEAs) provides an important tool for examining this neurotoxin. Changes in extracellular action potentials are readily observed and are dependent on synaptic function. Given the efficacy of murine frontal cortex and spinal cord networks to detect neuroactive substances, we investigated the effects of ω-agatoxin on spontaneous action potential firing within these networks. We found that networks derived from spinal cord are more sensitive to the toxin than those from frontal cortex; a concentration of only 10nM produced statistically significant effects on activity from spinal cord networks whereas 50nM was required to alter activity in frontal cortex networks. Furthermore, the effects of the toxin on frontal cortex are more complex as unit specific responses were observed. These manifested as either a decrease or increase in action potential firing rate which could be statistically separated as unique clusters. Administration of bicuculline, a GABAA inhibitor, isolated a single response to ω-agatoxin, which was characterized by a reduction in network activity. These data support the notion that the two clusters detected with ω-agatoxin exposure represent differential responses from excitatory and inhibitory neuronal populations.

Short Neuropeptide F Acts as a Functional Neuromodulator for Olfactory Memory in Kenyon Cells ofDrosophilaMushroom Bodies

In insects, many complex behaviors, including olfactory memory, are controlled by a paired brain structure, the so-called mushroom bodies (MB). In Drosophila, the development, neuroanatomy, and function of intrinsic neurons of the MB, the Kenyon cells, have been well characterized. Until now, several potential neurotransmitters or neuromodulators of Kenyon cells have been anatomically identified. However, whether these neuroactive substances of the Kenyon cells are functional has not been clarified yet. Here we show that a neuropeptide precursor gene encoding four types of short neuropeptide F (sNPF) is required in the Kenyon cells for appetitive olfactory memory. We found that activation of Kenyon cells by expressing a thermosensitive cation channel (dTrpA1) leads to a decrease in sNPF immunoreactivity in the MB lobes. Targeted expression of RNA interference against the sNPF precursor in Kenyon cells results in a highly significant knockdown of sNPF levels. This knockdown of sNPF in the Kenyon cells impairs sugar-rewarded olfactory memory. This impairment is not due to a defect in the reflexive sugar preference or odor response. Consistently, knockdown of sNPF receptors outside the MB causes deficits in appetitive memory. Altogether, these results suggest that sNPF is a functional neuromodulator released by Kenyon cells.

Organization of the Olfactory System of Nymphalidae Butterflies

Olfaction is in many species the most important sense, essential for food search, mate finding, and predator avoidance. Butterflies have been considered a microsmatic group of insects that mainly rely on vision due to their diurnal lifestyle. However, an emerging number of studies indicate that butterflies indeed use the sense of smell for locating food and oviposition sites. To unravel the neural substrates for olfaction, we performed an anatomical study of 2 related butterfly species that differ in food and host plant preference. We found many of the anatomical structures and pathways, as well as distribution of neuroactive substances, to resemble that of their nocturnal relatives among the Lepidoptera. The 2 species differed in the number of one type of olfactory sensilla, thus indicating a difference in sensitivity to certain compounds. Otherwise no differences could be observed. Our findings suggest that the olfactory system in Lepidoptera is well conserved despite the long evolutionary time since butterflies and moths diverged from a common ancestor.

Neurotransmitters and synaptic components in the Merkel cell–neurite complex, a gentle‐touch receptor

Merkel cells are an enigmatic group of rare cells found in the skin of vertebrates. Most make contacts with somatosensory afferents to form Merkel cell-neurite complexes, which are gentle-touch receptors that initiate slowly adapting type I responses. The function of Merkel cells within the complex remains debated despite decades of research. Numerous anatomical studies demonstrate that Merkel cells form synaptic-like contacts with sensory afferent terminals. Moreover, recent molecular analysis reveals that Merkel cells express dozens of presynaptic molecules that are essential for synaptic vesicle release in neurons. Merkel cells also produce a host of neuroactive substances that can act as fast excitatory neurotransmitters or neuromodulators. Here, we review the major neurotransmitters found in Merkel cells and discuss these findings in relation to the potential function of Merkel cells in touch reception.

Neuroprotective role of fibronectin in neuron-glial extrasynaptic transmission.

Most hypotheses concerning the mechanisms underlying Parkinson's disease are based on altered synaptic transmission of the nigrostriatal system. However, extrasynaptic transmission was recently found to affect dopamine neurotransmitter delivery by anisotropic diffusion in the extracellular matrix, which is modulated by various extracellular matrix components such as fibronectin. The present study reviewed the neuroprotective effect of fibronectin in extrasynaptic transmission. Fibronectin can regulate neuroactive substance diffusion and receptor activation, and exert anti- neuroinflammatory, adhesive and neuroprotective roles. Fibronectin can bind to integrin and growth factor receptors to transactivate intracellular signaling events such as the phosphatidylinositol 3-kinase/protein kinase B pathway to regulate or amplify growth factor-like neuroprotective actions. Fibronectin is assembled into a fibrillar network around cells to facilitate cell migration, molecule and ion diffusion, and even drug delivery and treatment. In addition, the present study analyzed the neuroprotective mechanism of fibronectin in the pathogenesis of Parkinson's disease, involving integrin and growth factor receptor interactions, and discussed the possible therapeutic and diagnostic significance of fibronectin in Parkinson's disease.

Evaluation of Caspase-1 Activation and IL-1β Production in A Kainic Acid Microdyalisis Brain Injury Model

Intracerebral infusion of kainic acid (KA) by a microdialysis probe induces a focal swelling in the brain-perfused area which promotes inflammation (Compan et al., 2012; Oprica et al., 2003). The microdialysis technique allows the local in vivo perfusion of KA and the simultaneous collection of inflammatory mediators, and other neuroactive substances, released in the injured brain. This protocol also allows the perfusion of different solutions in each cerebral hemisphere at the same time. By perfusing KA in isotonic solution of Krebs-Ringer Bicarbonate (KRB) (280-290 mOsm) in one hippocampus and KA in hypertonic KRB solution (1,400-1,500 mOsm) in the contralateral side, we can evaluate in vivo the efficiency of hypertonic solutions in preventing inflammation induced by swelling after KA infusion. Once the inflammatory response has been induced, it is possible to infuse through the microdialysis probe a biotinylated specific inhibitor of caspase-1 allowing the detection of the brain regions and cells involved in IL-1 production in response to the injury (Oprica et al., 2003).

Cell Transplantation as a Pain Therapy Targets Both Analgesia and Neural Repair

Cell transplantation is a potentially powerful approach for the alleviation of chronic pain. The strategy of cell transplantation for the treatment of pain is focused on cell-based analgesia and neural repair. (1) Adrenal medullary chromaffin cells and the PC12 cell line have been used to treat cancer pain and neuropathic pain in both animal models and human cases. As biological or living minipumps, these cells produce and secrete pain-reducing neuroactive substances if administered directly into the spinal subarachnoid space. (2) Cell implantation for pain neurorestorative therapy is a new concept and an emerging research field for pain control along with neural repair. Possible neurorestorative mechanisms include neuroprotective, neurotrophic, neuroreparative, neuroregenerative, neuromodulation, or neuroconstructive interventions, as well as immunomodulation and enhancing the microcirculation. These factors may ultimately restore the damaged or irritated condition of the lesioned nerves. The growing preclinical and clinical data show that neural stem/progenitor cells, olfactory ensheathing cells, mesenchymal stromal cells, and CD34(+) cells have the capacity to manage intractable pain and improve neurological functions. Cell delivery routes include local, intrathecal, or intravascular implants. Although these strategies are still in their infancy phase for pain neurorestoratology, cell-based therapies could open up new avenues for the relief of pain. In this review, these aspects are critically analyzed based on our own investigations. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Psychiatric Comorbidities in Temporal Lobe Epilepsy: Possible Relationships between Psychotic Disorders and Involvement of Limbic Circuits

Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

Characterization of tyramine β-hydroxylase, an enzyme upregulated by stress in Periplaneta americana

Octopamine (OA) is an important neuroactive substance that modulates several physiological functions and behaviors of various invertebrate species. This biogenic monoamine, structurally related to noradrenaline, acts as a neurotransmitter, a neuromodulator, or a neurohormone in insects. The tyramine β-hydroxylase (TBH) catalyzes the last step in OA biosynthesis and thus plays a key role in the regulation of synthesis and secretion of OA in neurons. The aim of this study was to characterize TBH in the cockroach Periplaneta americana and to get a better understanding of its regulation under stress conditions in this insect. First of all, five full-length cDNAs encoding TBH isoforms were cloned from the nerve cord of the physiological model P. americana. PaTBH transcripts were found mainly expressed in nervous tissues and in octopaminergic dorsal unpaired median neurons. In addition, a new ELISA assay was developed so as to allow determination of both OA level and TBH activity in stressed cockroaches. Mechanical stressful stimulation led to a significant increase in TBH activity after 1 and 24 h, with a higher induction after 1 h than after 24 h. Thus, TBH could be considered as a promising biomarker of stress in insects rather than OA.

Transcriptomic analysis of neuropeptides and peptide hormones in the barnacle Balanus amphitrite: evidence of roles in larval settlement.

The barnacle Balanus amphitrite is a globally distributed marine crustacean and has been used as a model species for intertidal ecology and biofouling studies. Its life cycle consists of seven planktonic larval stages followed by a sessile juvenile/adult stage. The transitional processes between larval stages and juveniles are crucial for barnacle development and recruitment. Although some studies have been conducted on the neuroanatomy and neuroactive substances of the barnacle, a comprehensive understanding of neuropeptides and peptide hormones remains lacking. To better characterize barnacle neuropeptidome and its potential roles in larval settlement, an in silico identification of putative transcripts encoding neuropeptides/peptide hormones was performed, based on transcriptome of the barnacle B. amphitrite that has been recently sequenced. Potential cleavage sites andstructure of mature peptides were predicted through homology search of known arthropod peptides. In total, 16 neuropeptide families/subfamilies were predicted from the barnacle transcriptome, and 14 of them were confirmed as genuine neuropeptides by Rapid Amplification of cDNA Ends. Analysis of peptide precursor structures and mature sequences showed that some neuropeptides of B. amphitrite are novel isoforms and shared similar characteristics with their homologs from insects. The expression profiling of predicted neuropeptide genes revealed that pigment dispersing hormone, SIFamide, calcitonin, and B-type allatostatin had the highest expression level in cypris stage, while tachykinin-related peptide was down regulated in both cyprids and juveniles. Furthermore, an inhibitor of proprotein convertase related to peptide maturation effectively delayed larval metamorphosis. Combination of real-time PCR results and bioassay indicated that certain neuropeptides may play an important role in cypris settlement. Overall, new insight into neuropeptides/peptide hormones characterized in this study shall provide a platform for unraveling peptidergic control of barnacle larval behavior and settlement process.

Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala

Recent in vitro evidence indicates that astrocytes can modulate synaptic plasticity by releasing neuroactive substances (gliotransmitters). However, whether gliotransmitter release from astrocytes is necessary for higher brain function in vivo, particularly for memory, as well as the contribution of connexin (Cx) hemichannels to gliotransmitter release, remain elusive. Here, we microinfused into the rat basolateral amygdala (BLA) TAT-Cx43L2, a peptide that selectively inhibits Cx43-hemichannel opening while maintaining synaptic transmission or interastrocyte gap junctional communication. In vivo blockade of Cx43 hemichannels during memory consolidation induced amnesia for auditory fear conditioning, as assessed 24 h after training, without affecting short-term memory, locomotion, or shock reactivity. The amnesic effect was transitory, specific for memory consolidation, and was confirmed after microinfusion of Gap27, another Cx43-hemichannel blocker. Learning capacity was recovered after coinfusion of TAT-Cx43L2 and a mixture of putative gliotransmitters (glutamate, glutamine, lactate, d-serine, glycine, and ATP). We propose that gliotransmitter release from astrocytes through Cx43 hemichannels is necessary for fear memory consolidation at the BLA. Thus, the present study is the first to demonstrate a physiological role for astroglial Cx43 hemichannels in brain function, making these channels a novel pharmacological target for the treatment of psychiatric disorders, including post-traumatic stress disorder.

Innervation of ventricular and periventricular brain compartments

Synaptic transmission is divided into two broad categories on the basis of the distance over which neurotransmitters travel. Wiring transmission is the release of transmitter into synaptic clefts in close apposition to receptors. Volume transmission is the release of transmitters or modulators over varying distances before interacting with receptors. One case of volume transmission over potentially long distances involves release into cerebrospinal fluid (CSF). The CSF contains neuroactive substances that affect brain function and range in size from small molecule transmitters to peptides and large proteins. CSF-contacting neurons are a well-known and universal feature of non-mammalian vertebrates, but only supra- and subependymal serotonergic plexuses are a commonly studied feature in mammals. The origin of most other neuroactive substances in CSF is unknown. In order to determine which brain regions communicate with CSF, we describe the distribution of retrograde neuronal labeling in the rat brain following ventricular injection of Cholera toxin, ß subunit (CTß), a tracer frequently used in brain circuit analysis. Within 15 to 30min following intraventricular injection, there is only diffuse, non-specific staining adjacent to the ventricular surface. Within 2 to 10days, however, there is extensive labeling of neuronal perikarya in specific nuclear groups in the telencephalon, thalamus, hypothalamus and brainstem, many at a considerable distance from the ventricles. These observations support the view that ventricular CSF is a significant channel for volume transmission and identifies those brain regions most likely to be involved in this process.

The extracellular matrix and diffusion barriers in focal cortical dysplasias

Focal cortical dysplasias (FCDs) of the brain are recognized as a frequent cause of intractable epilepsy. To contribute to the current understanding of the mechanisms of epileptogenesis in FCD, our study provides evidence that not only cellular alterations and synaptic transmission, but also changed diffusion properties of the extracellular space (ECS), induced by modified extracellular matrix (ECM) composition and astrogliosis, might be involved in the generation or spread of seizures in FCD. The composition of the ECM in FCD and non-malformed cortex (in 163 samples from 62 patients) was analyzed immunohistochemically and correlated with the corresponding ECS diffusion parameter values determined with the real-time iontophoretic method in freshly resected cortex (i.e. the ECS volume fraction and the geometrical factor tortuosity, describing the hindrances to diffusion in the ECS). The ECS in FCD was shown to differ from that in non-malformed cortex, mainly by the increased accumulation of certain ECM molecules (tenascin R, tenascin C, and versican) or by their reduced expression (brevican), and by the presence of an increased number of astrocytic processes. The consequent increase of ECS diffusion barriers observed in both FCD type I and II (and, at the same time, the enlargement of the ECS volume in FCD type II) may alter the diffusion of neuroactive substances through the ECS, which mediates one of the important modes of intercellular communication in the brain - extrasynaptic volume transmission. Thus, the changed ECM composition and altered ECS diffusion properties might represent additional factors contributing to epileptogenicity in FCD.

Behavioral and physiological responses to central administration of corticotropin-releasing factor in the bluebanded goby (Lythrypnus dalli)

Central manipulation of neuromodulators is critical to establishing causal links between brain function and behavioral output. The absence of a rigorous method of evaluating intracerebroventricular (icv) injection efficacy in small model organisms is one reason why peripheral administration of neuroactive substances is more common. We use the bluebanded goby (Lythrypnus dalli), a small, highly social fish, to 1) validate our method of icv injection by testing the hypothesis that corticotropin-releasing factor (CRF) elevates ventilation rate (VR) and 2) propose a novel bioassay using basal physiology and behavior during recovery from anesthesia/icv administration to assess injection efficacy, neuromodulator activity, and procedural confounds. Central CRF administration significantly increased ventilation rate, demonstrating successful delivery of CRF to the brain. There were no significant differences in cortisol among treatments. The injection procedure did, however, decouple the temporal relationship between the initiation of ventilation and time to regain equilibrium present in control fish. Importantly, neither icv vehicle nor CRF injection affected the initiation of ventilation, disrupted the stereotyped recovery pattern following anesthesia, or initiated an endocrine stress response. Taken together, we suggest that 1) icv injection can be effectively used to manipulate central levels of CRF in L. dalli and 2) physiological and behavioral recovery from anesthesia may be used to evaluate injection/technique efficacy. We will use these data in future studies as a measure of effective CRF delivery, to allow for appropriate recovery from icv injection, and to better evaluate independent effects of CRF on social and/or sexual behavior.

Volume Transmission–Mediated Encephalopathies

There is strong evidence that the composition of cerebrospinal fluid (CSF) influences brain development, neurogenesis, and behavior. The bidirectional exchange of CSF and interstitial fluid (ISF) across the ependymal and pia-glial membranes is required for these phenomena to occur. Because ISF surrounds the parenchymal compartment, neuroactive substances in the CSF and ISF can influence neuronal activity. Functionally important neuroactive substances are distributed to distant sites of the central nervous system by the convection and diffusion of CSF and ISF, a process known as volume transmission. It has recently been shown that pathologically altered CSF from patients with acute traumatic brain injury suppresses in vitro neuronal network activity (ivNNA) recorded by multielectrode arrays measuring synchronously bursting neural populations. Functionally relevant substances in pathologically altered CSF have been biochemically identified, and ivNNA has been partially recovered by pharmacologic intervention. It remains unclear whether the in vivo parenchymal compartment remains unaffected by pathologically altered CSF that significantly impairs ivNNA. We hypothesize that pathologic CSF alterations are not just passive indicators of brain diseases but that they actively and directly evoke functional disturbances in global brain activity through the distribution of neuroactive substances, for instance, secondary to focal neurologic disease. For this mechanism, we propose the new term volume transmission-mediated encephalopathies (VTE). Recording ivNNA in the presence of pure human CSF could help to identify and monitor functionally relevant CSF alterations that directly result in VTEs, and the collected data might point to therapeutic ways to antagonize these alterations.

Comparative neuroanatomy of Caudofoveata, Solenogastres, Polyplacophora, and Scaphopoda (Mollusca) and its phylogenetic implications

The nervous system of invertebrates is considered to be a very conservative organ system and thus can be helpful to elucidate questions of phylogenetic relationships. Up to now, comparative neuroanatomical studies have been mainly focused on arthropods, where in-depth studies on major brain structures are abundant. In contrast, except for Gastropoda and Cephalopoda, the nervous system of representatives of the second largest phylum of invertebrates, the Mollusca, is as yet hardly investigated. We therefore initiated an immunohistochemical survey to contribute new neuroanatomical data for several molluscan taxa, especially the lesser known Caudofoveata, Solenogastres, Polyplacophora, and Scaphopoda, focusing on the cellular architecture and distribution of neurotransmitters in the brain. Antisera against the widespread neuroactive substances FMRFamide and serotonin were used to label subsets of neurons. Both antisera were additionally used in combination with acetylated α-tubulin and the nuclear marker DAPI. This enables us to describe the morphology of the nervous system at a fine resolution and to compare its cellular architecture between different species of one taxon, as well as between different taxa of mollusks. On the basis of these results, the nervous system of caudofoveates seems to be most highly derived within the so-called basal (non-conchiferan) mollusks, and a monophyly of a clade Aplacophora could not be confirmed. In general, the brain as well as the remaining nervous system of the molluscan taxa investigated shows a great variability, suggesting a deep time origin of the diversification of this prominent protostome clade.

Plant Terpenoids: Acute Toxicities and Effects on Flight Motor Activity and Wing Beat Frequency in the Blow Fly Phaenicia sericata

We evaluated the acute toxicities and the physiological effects of plant monoterpenoids (eugenol, pulegone, citronellal and alpha-terpineol) and neuroactive insecticides (malathion, dieldrin and RH3421) on flight muscle impulses (FMI) and wing beat signals (WBS) of the blow fly (Phaenicia sericata). Topically-applied eugenol, pulegone, citronellal, and alpha-terpineol produced neurotoxic symptoms, but were less toxic than malathion, dieldrin, or RH3421. Topical application of eugenol, pulegone, and citronellal reduced spike amplitude in one of the two banks of blow fly dorsolongitudinal flight muscles within 6-8 min, but with citronellal, the amplitude of FMIs reverted to a normal pattern within 1 hr. In contrast to pulegone and citronellal, where impulse frequency remained relatively constant, eugenol caused a gradual increase, then a decline in the frequency of spikes in each muscle bank. Wing beating was blocked permanently within 6-7 min of administering pulegone or citronellal and within 16 mins with eugenol. alpha-Terpineol-treated blow flies could not beat their wings despite normal FMI patterns. The actions of these monoterpenoids on blow fly flight motor patterns are discussed and compared with those of dieldrin, malathion, RH3421, and a variety of other neuroactive substances we have previously investigated in this system. Eugenol, pulegone and citronellal readily penetrate blow fly cuticle and interfere with flight muscle and/or central nervous function. Although there were differences in the effects of these compounds, they mainly depressed flight-associated responses, and acted similarly to compounds that block sodium channels and facilitate GABA action.

Gut bacteria and brain function: The challenges of a growing field

In a recent article, Bravo et al. (1) demonstrated antidepressant and anxiolytic-like properties of a probiotic Lactobacillus rhamnosus in mice. Evidence for an involvement of the vagus nerve and the central gamma-aminobutyric acid (GABA) system in the modulation of emotional behavior by these bacteria was also provided. Overall, this is a commendable piece of work that has made an early and significant contribution to the increasingly fashionable exploration of, what the authors refer to as, the microbiome–gut–brain axis. However, this is just one story. Earlier, Bercik et al. (2) showed that the proliferation of lactobacilli and bifidobacteria naturally residing in the mouse gut also increased non-anxious behavior, but independently of the vagus nerve. The possibility that bacteria-derived neuroactive substances were involved was suggested and has precedents (2). It is likely, therefore, that research in this field is destined to be fraught with complexities such as these. So, what are the research priorities and the possible strategies that will reveal the full therapeutic potential of nurturing gut bacteria?

Responsiveness of a patient in a persistent vegetative state after a coma to weekly injections of autologous activated immune cells: a case report

IntroductionAn 82-year-old Caucasian woman had remained in a persistent vegetative state after a coma of seven months duration, which occurred after a stroke with hemiplegia, nine years previously. The persistent vegetative state could be reversed in part by weekly injections with activated immune cells. After therapy, our patient responded to commands in addition to regaining spontaneous movements of both arms and the ability to swallow. This is the first report on the treatment with activated immune cells of a patient in a persistent vegetative state after a coma.Case presentationAn 82-year-old Caucasian woman presented with a persistent vegetative state subsequent to a coma. She retained respiratory and autonomic functions. As contact was not possible, physiotherapy was passive. Her skin was yellowish, and our patient did not move by herself. Vomiting repeatedly resulted from tube feeding. After a once-weekly treatment with activated immune cells sampled from our patient's blood and activated in vitro, several of her functions gradually returned. Our patient opened her eyes in the requested direction and turned her head toward people entering the room. She 'supported' nursing efforts, as the nurse noted a loss of spastic motions. The strength in both her arms returned, and she spontaneously moved her arm on the side experiencing hemiplegia. After three months, our patient could stick out her tongue upon demand. Finally, the swallow reflexes of our patient started to return. However, tube feeding was continued, and our patient died after aspiration of vomit following a feeding.ConclusionThe success of treatment with autologous activated immune cells in this patient may have resulted from the production of neuroactive substances, such as neurotrophin-3 and brain-derived neurotrophic factor, by activated immune cells. The deterioration of our patient could be reversed, as demonstrated by the restoration of motor strength in her hemiplegic side. In addition, our patient was able to induce motor responses upon request. It seems reasonable to conclude that activated immune cells may improve the chronic vegetative state in some patients.