PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “synaptic dysfunction”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,207 records · Page 67Linked to original sources
PubMed1997

Effects of nefiracetam on amnesia animal models with neuronal dysfunctions.

The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide (nefiracetam; DM-9384), on learning and memory in several amnesia animal models with neuronal dysfunctions were investigated. Nefiracetam improved scopolamine-, bicuculline-, picrotoxin-, ethanol-, chlordiazepoxide- and cycloheximide-induced amnesia. Anti-amnesic action of nefiracetam on scopolamine model was antagonized by nifedipine and flunarizine, but not by diltiazem. Repeated administration of nefiracetam to AF64A-treated animals improved impairment of learning and memory as well as the alterations in cholinergic and monoaminergic neurotransmitters in the hippocampus. Basal forebrain (BF) lesioned rats induced by excitotoxin or by thermal coagulation showed impairment of learning accompanied by a marked reduction in choline acetyltransferase (ChAT) and acetylcholine esterase activities. Nefiracetam improved the learning deficit of the BF-lesioned rats. Nefiracetam also improved the carbon monoxide-induced delayed and acute amnesia. Nefiracetam stimulated acetylcholine release in the frontal cortex. Repeated administration of nefiracetam increased ChAT activity, gamma-aminobutyric acid (GABA) turnover and glutamic acid decarboxylase activity, and facilitated the Na(+)-dependent high-affinity GABA uptake. Nefiracetam activated the high voltage-activated (N/L-type) Ca2+ channel. The dose-response curves of nefiracetam were bell-shaped in both behavioral and biochemical studies. Therefore, it is suggested that nefiracetam improves the dysfunction of cholinergic, GABAergic and/or monoaminergic neuronal function by acting at Ca2+ channel and enhancing the release of neurotransmitters, and modifies impairment of memory processes induced by drugs and hypoxia.

Amnesia↗
PubMed2002

Regulation of acetylcholine synthesis and storage.

Acetylcholine is one of the major modulators of brain functions and it is the main neurotransmitter at the peripheral nervous system. Modulation of acetylcholine release is crucial for nervous system function. Moreover, dysfunction of cholinergic transmission has been linked to a number of pathological conditions. In this manuscript, we review the cellular mechanisms involved with regulation of acetylcholine synthesis and storage. We focus on how phosphorylation of key cholinergic proteins can participate in the physiological regulation of cholinergic nerve-endings.

Acetylcholine↗
PubMed2026

Genetic and molecular evidence linking CTSH to Alzheimer's disease pathophysiology.

INTRODUCTION: Lysosomal dysfunction contributes to Alzheimer's disease (AD) by impairing protein clearance and promoting neuroinflammation. Cathepsin H (CTSH), a lysosomal protease, recently emerged as a protective AD locus. We investigated how CTSH is regulated and how it influences early AD pathophysiology. METHODS: We analyzed genomic, transcriptomic, and proteomic data from cerebrospinal fluid (CSF) and brain tissue across three independent clinical and post mortem cohorts to assess CTSH regulation, expression, and disease associations. RESULTS: The coding variant rs2289702 acts as a cis-regulatory variant, altering CTSH mRNA and protein levels. The T allele associates with better cognition and reduced amyloid plaque burden. CSF CTSH correlates with total tau, phosphorylated tau181, neuronal markers, and multiple glial and complement-related inflammatory proteins. DISCUSSION: CTSH tracks early neurodegenerative, synaptic, and inflammatory changes, and co-expression analyses link it to broader immune-metabolic pathways. The findings position CTSH as a genetically regulated contributor to AD pathophysiology.

Humans↗
PubMed2005

Brain response to injury and neurodegeneration: endogenous neuroprotective signaling.

Synaptic activity and ischemia/injury promote lipid messenger formation through phospholipase-mediated cleavage of specific phospholipids from membrane reservoirs. Lipid messengers modulate signaling cascades, contributing to development, differentiation, function (e.g., memory), protection, regeneration, and repair of neurons and overall regulation of neuronal, glial, and endothelial cell functional integrity. Oxidative stress disrupts lipid signaling and promotes lipid peroxidation and neurodegeneration. Lipid signaling at the neurovascular unit (neurons, astrocytes, oligodendrocytes, microglia, and cells of the microvasculature) is altered in early cerebrovascular and neurodegenerative disease. We discuss how lipid signaling regulates critical events in neuronal survival. Aberrant synaptic plasticity (e.g., epileptogenesis) is highlighted to show how gene expression may drive synaptic circuitry formation in the "wrong" direction. Docosahexaenoic acid has been implicated in memory, photoreceptor cell biogenesis and function, and neuroprotection. Free docosahexaenoic acid released in the brain during experimental stroke leads to the synthesis of stereospecific messengers through oxygenation pathways. One messenger, 10,17S-docosatriene (neuroprotectin D1; NPD1), counteracts leukocyte infiltration and proinflammatory gene expression in brain ischemia-reperfusion. In retina, photoreceptor survival depends on retinal pigment epithelial (RPE) cell integrity. NPD1 is synthesized in RPE cells undergoing oxidative stress, potently counteracts oxidative stress-triggered apoptotic DNA damage in RPE, upregulates antiapoptotic proteins Bcl-2 and Bcl-x(L), and decreases proapoptotic Bax and Bad expression. These findings expand our understanding of how the nervous system counteracts redox disturbances, mitochondrial dysfunction, and proinflammatory conditions. The specificity and potency of NPD1 indicate a potential target for therapeutic intervention for stroke, age-related macular degeneration, spinal cord injury, and other neuroinflammatory or neurodegenerative diseases.

Animals↗
PubMed2002

Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity.

NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia, and pharmacological and genetic approaches have been used to model such dysfunction. We previously have described two mouse lines carrying point mutations in the NMDA receptor glycine binding site, Grin1(D481N) and Grin1(K483Q), which exhibit 5- and 86-fold reductions in receptor glycine affinity, respectively. Grin1(D481N) animals exhibit a relatively mild phenotype compatible with a moderate reduction in NMDA receptor function, whereas Grin1(K483Q) animals die shortly after birth. In this study we have characterized compound heterozygote Grin1(D481N/K483Q) mice, which are viable and exhibited biphasic NMDA receptor glycine affinities compatible with the presence of each of the two mutated alleles. Grin1(D481N/K483Q) mice exhibited a marked NMDA receptor hypofunction revealed by deficits in hippocampal long-term potentiation, which were rescued by the glycine site agonist d-serine, which also facilitated NMDA synaptic currents in mutant, but not in wild-type, mice. Analysis of striatal monoamine levels revealed an apparent dopaminergic and serotonergic hyperfunction. Behaviorally, Grin1(D481N/K483Q) mice were insensitive to acute dizocilpine pretreatment and exhibited increased startle response but normal prepulse inhibition. Most strikingly, mutant mice exhibited a sustained, nonhabituating hyperactivity and increased stereotyped behavior that were resistant to suppression by antipsychotics and the benzodiazepine site agonist Zolpidem. They also displayed a disruption of nest building behavior and were unable to perform a cued learning paradigm in the Morris water maze. We speculate that the severity of NMDA receptor hypofunction in these mice may account for their profound behavioral phenotype and insensitivity to antipsychotics.

Animals↗
PubMed2002

Abnormal phosphorylation of synapsin I predicts a neuronal transmission impairment in the R6/2 Huntington's disease transgenic mice.

Motor and cognitive deficits in Huntington's disease (HD) are likely caused by progressive neuronal dysfunction preceding neuronal cell death. Synapsin I is one of the major phosphoproteins regulating neurotransmitter release. We report here an abnormal phosphorylation state of synapsin I in the striatum and the cerebral cortex of R6/2 transgenic mice expressing the HD mutation. These changes are mostly characterized by an early overphosphorylation at sites 3-5, whereas phosphorylation at site 1 remains unchanged and at site 6 becomes reduced only close to the end stage of the disease. Such changes do not result from modification in protein expression levels. However, we show a decreased expression of the calcineurin regulatory subunit-B, which may contribute to an imbalance between kinase and phosphatase activities. Together the results suggest that an early impairment in synapsin phosphorylation-dephosphorylation may alter synaptic vesicle trafficking and lead to defective neurotransmission in HD.

Animals↗
PubMed1985

Possible involvement of dynorphinergic system in nociceptive transmission at spinal level.

The opioid peptide dynorphin1-32 (DYN1-32, 25 nmol) intrathecally administered causes, in the rat, an elevation of nociceptive threshold of longer duration than that of DYN A, as ascertained by vocalization test. Comparative findings obtained with tail flick test allow to differentiate antinociception from motor dysfunction. The breakdown of DYN A at spinal level is very rapid. The electrical stimulation of the tail associated to a restraint condition of the rat produces a significant increase of immunoreactive DYN in cervical, thoracic and lumbar segments of spinal cord, therefore indicating a correlative, if not causal, relationship between the spinal dynorphinergic system and aversive stimuli.

Analgesics↗
PubMed2004

[The intermediate syndrome during organophosphorus pesticide poisoning].

Acute intoxication by organophosphate pesticides is frequent in Morocco. We report two cases of malathion poisoning complicated by intermediate syndrome. The purpose of this work is to describe distinctive features of this syndrome, it arises 48-96 h after the cholinergic crisis and it is characterized by respiratory paresis with difficulties of weaning from the assisted respiratory, deficit of proximal limbs, neck flexors, and cranial nerves. This syndrome coincides with the prolonged inhibition of the acetylcholinesterase, and is not due to the necrosis of muscular fiber's necrosis. Both clinical and electromyographic features are explained by a combined pre- and postsynaptic dysfunction of the neuromuscular transmission. The difficulty of this syndrome lies in its rarity and also its severity, because of the respiratory failure, which justifies medical supervision in intensive care unit, for at least 96 h, in expectation for the respiratory distress, all the more cholinergic syndrome is intense.

Adult↗
PubMed2000

Schizophrenia and the mechanisms of conscious integration.

This article considers the possibility that defective interactions among distributed brain areas may underlie certain dysfunctions of conscious integration such as those seen in schizophrenia. Recent experimental evidence obtained using whole-head magnetoencephalography during binocular rivalry is first reviewed. The results outline a cortical network that underlies conscious integration in the normal brain. This network is not localized to a small part of the brain but it is distributed over frontal, parietal, temporal, and occipital areas. Large-scale simulations of the dynamics of thalamocortical integration are then examined. These studies indicate that several factors can affect the rapid integration of the activity of distributed thalamocortical regions and the resulting behavioral performance. These simulations show that an altered dynamics of corticothalamic and corticocortical re-entrant circuits can result from increased conduction delays, blockade of voltage-dependent connections, reduced synaptic density, and disruptions of the local connectivity within a single cortical area. It can also result from alterations in the activity of diffuse ascending systems that lead to defective reinforcement of integrated activity patterns. Finally, the article briefly reviews theoretical measures of the integration of multiple brain areas, such as measures of functional clustering. These measures have been applied to PET data obtained from schizophrenic subjects and controls while performing cognitive tasks. The results show a change in the functional interactions among distributed brain areas in schizophrenics despite the absence of a change in activation patterns. The possibility is raised that disruption of re-entrant interactions among cortical areas may contribute to the pathophysiology of schizophrenia.

Brain↗
PubMed1991

Growth and development of the brain in Down syndrome.

The brain of a child with Down syndrome develops differently from a normal one, attaining a form reduced in size and altered in configuration. Directly related to the mental retardation are neuronal modifications manifest as alterations of cortical lamination, reduced dendritic ramifications, and diminished synaptic formation. However, selected cholinergic marker enzymes such as choline acetyl transferase and acetyl cholinesterase have shown no alterations in young children with Down syndrome. The pace of the neuronal transformations is related to stage of maturation. With early growth and development, the normal dendritic tree continuously expands. In Down syndrome, at 4 months of age, the neurons show a relatively expanded dendritic tree, but during the first year the dendrites stop growing and become atrophic relative to control neurons. Accompanying these neuronal irregularities are subtle alterations of other cell types: astrocyte, oligodendrogliocyte, microglia, and endothelial cell. In early infancy, one of the astrocytic markers, GFAP, is not altered, but there is greater expression of S-100 protein in the temporal lobe in Down syndrome. Oligodendrogliocyte dysfunction is reflected in delayed myelination in pathways of frontal and temporal lobes. Microglia appear more prominent in Down syndrome. A minority of children with Down syndrome have vascular dysplasias and focal calcification of basal ganglia. In young children, expression of beta-amyloid in Down syndrome is no different than in normal children but disappears after age two, only to reappear in adults. As some of these studies suggest, the identification of genes on chromosome 21 and the determination of the gene product allow the production of specific antibodies and, through immunohistochemical techniques, the identification of the expression of these proteins in both normal development and Down syndrome. Specifically, the localization and appearance in development of proteins such as the beta-subunit of S-100, beta-amyloid (A4 protein), superoxide dismutase, and OK-2 are providing the means for better understanding the morphogenesis of the cellular and eventually molecular basis for the mental retardation in Down syndrome.

Acetylcholinesterase↗
PubMed2001

gamma-Aminobutyric acid(A) neurotransmission and cerebral ischemia.

In this review, we present evidence for the role of gamma-aminobutyric acid (GABA) neurotransmission in cerebral ischemia-induced neuronal death. While glutamate neurotransmission has received widespread attention in this area of study, relatively few investigators have focused on the ischemia-induced alterations in inhibitory neurotransmission. We present a review of the effects of cerebral ischemia on pre and postsynaptic targets within the GABAergic synapse. Both in vitro and in vivo models of ischemia have been used to measure changes in GABA synthesis, release, reuptake, GABA(A) receptor expression and activity. Cellular events generated by ischemia that have been shown to alter GABA neurotransmission include changes in the Cl(-) gradient, reduction in ATP, increase in intracellular Ca(2+), generation of reactive oxygen species, and accumulation of arachidonic acid and eicosanoids. Neuroprotective strategies to increase GABA neurotransmission target both sides of the synapse as well, by preventing GABA reuptake and metabolism and increasing GABA(A) receptor activity with agonists and allosteric modulators. Some of these strategies are quite efficacious in animal models of cerebral ischemia, with sedation as the only unwanted side-effect. Based on promising animal data, clinical trials with GABAergic drugs are in progress for specific types of stroke. This review attempts to provide an understanding of the mechanisms by which GABA neurotransmission is sensitive to cerebral ischemia. Furthermore, we discuss how dysfunction of GABA neurotransmission may contribute to neuronal death and how neuronal death can be prevented by GABAergic drugs.

Adenosine Triphosphate↗
PubMed2026

CACNA1C Genetic Variants Differentially Affect Neuronal Networks Through Divergent Pathways.

BACKGROUND: CACNA1C encodes the pore-forming subunit of the L-type calcium channel Cav1.2. Common variants in CACNA1C are associated with psychiatric disorders, whereas rare single nucleotide variants cause CACNA1C-related disorder, a multisystem disorder with symptoms that include autism spectrum disorder (ASD), intellectual disability, and seizures. However, the cellular mechanisms linking CACNA1C dysfunction to neurodevelopmental phenotypes remain poorly understood. METHODS: We generated isogenic CACNA1C loss-of-function induced pluripotent stem cell lines and reprogrammed a line from an individual carrying a novel predicted gain-of-function variant (p.Ala1521Pro) in CACNA1C. Neuronal activity was assessed using multielectrode arrays, pharmacological manipulation, and gene expression analysis. Early developmental phenotypes were examined using quantitative reverse transcriptase polymerase chain reaction, immunocytochemistry, and RNA sequencing. RESULTS: Neurons carrying CACNA1C variants displayed opposing alterations in network dynamics, depending on variant type. Pharmacological and molecular assays indicated that these network differences were associated with dysregulated GABAergic (gamma-aminobutyric acidergic) signaling. Early developmental analysis revealed that loss of CACNA1C altered rosette morphology, CREB (cAMP response element binding protein) phosphorylation, and transcriptional programs related to axonogenesis and synaptic signaling, indicating effects on neuronal differentiation. The patient line exhibited opposing effects on rosette morphology and CREB signaling, reflecting variant-specific effects. CONCLUSIONS: These findings demonstrate that Cav1.2 regulates excitatory-inhibitory balance, network organization, and aspects of neurodevelopment. Divergent effects of CACNA1C variants highlight how altered Cav1.2 signaling contributes to variable neurodevelopmental phenotypes, including ASD and epilepsy, and establish a framework for defining CACNA1C variant effects in human neurons.

CACNA1C↗
PubMedDate not supplied

Alzheimer's disease as a loss of differentiation control in a subset of neurons that retain immature features in the adult brain.

Degeneration in AD primarily occurs in a subset of neurons that in the adult brain retain a high degree of structural plasticity and in these neurons is associated with the activation of mitogenic pathways and a cell cycle re-entry. Brain areas affected by AD pathology are those structures involved in the regulation of "higher brain functions" that become increasingly predominant as the evolutionary process of encephalization progresses, such as hippocampus, neocortical association areas and the cholinergic basal forebrain neurons. The functions these areas subserve such as learning, memory, perception, self-awareness, and consciousness require a life-long re-fitting of synaptic contacts that allows for the acquisition of new epigenetic information. This adaptive reorganization of neuronal connectivity in the mature brain is based upon the strengthening of existing synapses, the formation of new synapses and the destabilization of previously established synaptic contacts. With the increasing need during evolution to organize brain structures of increasing complexity, these processes of dynamic stabilization and de-stabilization become more and more important but might also provide the basis for an increasing rate of failure. A hypothesis is proposed that it is the 'labile state of differentiation' (G0-arrest) of a subset of neurons in the adult brain that allows for ongoing morphoregulatory processes after development is completed but at the same time renders these neurons particularly vulnerable. The delicate balance between G0-arrest and G1-entry might be prone to a variety of potential disturbances during the lifetime of an individual. Morphodysregulation in AD, accompanied by an activation of intracellular mitogenic signaling might, thus, be a slowly progressing dysfunction that eventually overrides the differentiation control and results in dedifferentiation, a condition in conflict with the otherwise 'mature' background of the nervous system. Cell-cycle and differentiation control might thus provide the link between structural brain self-organization and neurodegeneration that both are unique to human.

Adult↗
PubMed1998

Postmortem studies in schizophrenia.

The past decade has seen renewed interest in the neuropathology of schizophrenia. The advent of new postmortem techniques and functional imaging, along with a greater understanding of the neuropsychology of schizophrenia, have provided many new clues to the nature of the underlying brain dysfunction in this disorder. There has also been a greater understanding of the presence of severe cognitive dysfunction among many elderly persons with schizophrenia. In this article, a series of investigations are described that seek to answer basic questions about the neuropathology of schizophrenia, in particular as it pertains to cognitive impairment. The first study describes neuropathological findings in 100 consecutively autopsied persons with schizophrenia, the majority of whom had had detailed antemortem assessments. Results from this first study prompted the conclusion that schizophrenia is not characterized by classical, histologically identifiable neuropathology. Moreover, most cases of dementia in schizophrenia are probably not the result of neuropathologically identifiable dementing illnesses. The next four studies examined chemical markers that are altered in Alzheimer's disease and some other dementing conditions and have also been suggested to be abnormal in schizophrenia: choline acetyltransferase, catecholamines and indolamines, neuropeptides, and synaptic proteins. Schizophrenia cases as a group did not show a cholinergic deficit; nor did they differ from elderly comparison cases with respect to cortical catecholamines and indolamines. Among the schizophrenia cases, however, cognitive impairment was negatively correlated with choline acetyltransferase activity. Those with cognitive impairment showed evidence of cortical noradrenergic and serotonergic deficits. Neuropeptide deficits were also present in schizophrenia, but their pattern differed from that seen in Alzheimer's disease. Increased synaptic protein activity was found in the cingulate cortex of persons with schizophrenia, and this activity was correlated with schizophrenia symptoms. From this second series of studies, it was concluded that some biological measures in schizophrenia may be related to cognitive impairment (e.g., cortical amines), whereas others may be related to diagnosis (e.g., neuropeptide deficits). In addition, synaptic organization may correlate with schizophrenia symptoms.

Aged↗
PubMed1996

Dopamine transporter (Dat) and synaptic vesicle amine transporter (VMAT2) gene expression in the substantia nigra of control and Parkinson's disease.

The cellular expression of DAT mRNA and VMAT2 mRNA was investigated in sections of the human post-mortem substantia nigra in control and Parkinson's disease tissue using in situ hybridisation techniques. Short synthetic oligodeoxynucleotides were used to detect these gene transcripts at the cellular level. In the control human nigra, high levels of expression were seen in all sub-divisions of the substantia nigra, especially within medial regions. By contrast, the level of expression of both DAT mRNA and VMAT2 mRNA was markedly reduced in Parkinson's disease; these reductions in hybridisation signal were associated with (i) a marked loss of dopamine-containing cells in the substantia nigra, and (ii) a reduction in both DAT and VMAT2 signal per cell in the remaining pigmented neurones. These disease-related decreases in the cellular abundance of both DAT and VMAT2 gene transcripts in the surviving cells of the parkinsonian nigra may reflect compensatory changes in catecholamine signalling or may be a consequence of neuronal dysfunction.

Aged↗
PubMed2006

Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death.

Glutamate neurotransmitter action on postsynaptic receptors is terminated by its clearance from the synaptic cleft by transporter proteins located in neurons and glial cells. Failure of glutamate removal can lead to neuronal death due to its well-known neurotoxic properties. Glutamate transporters are dependent on external Na+, and thus on the activity of Na+/K+ ATPases, which maintain the Na+ concentration gradient. When the energy brain requirements are not fulfilled by the appropriate blood supply of glucose and oxygen, the Na+ gradient collapses leading to impaired glutamate and aspartate removal, or even to the release of these amino acids through the reverse operation of their transporters. Such a scenario would be associated with brain ischemia and hypoglycemia due to the prompt decline in ATP levels. In addition, some evidence suggests that downregulation of glutamate transporters after the ischemic period, or the dysfunction induced by oxidation, contributes to the accumulation of extracellular glutamate and neuronal death. Neuronal damage is associated with excitotoxicity, a type of cell death triggered by the overactivation of glutamate receptors and the loss of calcium homeostasis. Throughout this review we will discuss recent evidence suggesting that failure of glutamate transport during ischemia contributes to the elevation of extracellular glutamate and to the induction of excitotoxicity. We will also discuss the contribution of glial vs. neuronal glutamate transporters in ischemic damage, and the involvement of the different glutamate transporter subtypes. We will focus on experimental data from rodent models, because many of the studies on glutamate transport and ischemic damage have been performed in these animal species.

Animals↗
PubMed2000

Toxin 2 (PhTx2), a neurotoxic fraction from Phoneutria nigriventer spider venom, causes acute morphological changes in mouse skeletal muscle.

Phoneutria nigriventer (Labidognatha, Ctenidae) is a spider found in the warm regions of South America. Bites by this species cause intense local pain, autonomic dysfunction and paralysis. PhTx2, a neurotoxic fraction of the venom of this species, interferes with the physiology of sodium channel function. The present study describes the morphological changes in mouse phrenic nerve and diaphragm muscle after 15, 30, 45 and 60 min of incubation with 1 microg of PhTx2/ml. Light and transmission electron microscopy showed that PhTx2 caused progressive myonecrosis which involved swelling of the sarcoplasmic reticulum, mitochondrial damage, disorganization of the sarcomeres, zones of hypercontracted myofibrils and rupture of the plasma membrane. The intramuscular fascicles of the phrenic nerve showed vacuolated myelinated axons and Schwann cells. The neuromuscular junctions had vesicle-depleted nerve terminals with swollen mitochondria. The axolema was frequently invaginated and sequestered portions of the axoplasm, or was sometimes interrupted at the site of the synaptic gutter. The post-synaptic junctional folds were shallow and disperse. These morphological alterations in the muscle and nerve fibres were similar to those caused by osmotic disturbances and agree with the ability of PhTx2 to increase the permeability of sodium channels. An increase in sodium influx would probably be accompanied by an influx of water and an elevation in the concentration of cytosolic calcium as a result of calcium release by the sarcoplasmic reticulum and/or mitochondria and the entry of extracellular calcium. The morphological effects caused by PhTx2 were comparable to those seen with Phoneutria nigriventer whole venom which is known to activate and to delay the inactivation of sodium channels. We conclude that PhTx2 is probably the main toxic fraction responsible for such morphological alterations.

Animals↗