Mol.Pharm.
Stimulatory effects of delta-hexachlorocyclohexane on Ca(2+)-activated K(+) currents in GH(3) lactotrophs.

Wu SN, Li HF, Chiang HT

Department of Medical Education and Research, Veterans General Hospital, Kaohsiung, Taiwan, Republic of China. snwu@isca.vghks.gov.tw

delta-Hexachlorocyclohexane (delta-HCH), a lipophilic neurodepressant agent, has been shown to inhibit neurotransmitter release and stimulate ryanodine-sensitive Ca(2+) channels. However, the effect of delta-HCH on neuronal activity remains unclear, although it may enhance the gamma-aminobutyric acid-induced current. Its effects on ionic currents were investigated in rat pituitary GH(3) cells and human neuroblastoma IMR-32 cells. In GH(3) cells, delta-HCH increased the amplitude of Ca(2+)-activated K(+) current (I(K(Ca))). delta-HCH (100 microM) slightly inhibited the amplitude of voltage-dependent K(+) current. delta-HCH (30 microM) suppressed voltage-dependent L-type Ca(2+) current (I(Ca, L)), whereas gamma-HCH (30 microM) had no effect on I(Ca, L). In the inside-out configuration, delta-HCH applied intracellularly did not change the single channel conductance of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels; however, it did increase the channel activity. The delta-HCH-mediated increase in the channel activity is mainly mediated by its increase in the number of long-lived openings. delta-HCH reversibly increased the activity of BK(Ca) channels in a concentration-dependent manner with an EC(50) value of 20 microM. delta-HCH also caused a left shift in the midpoint for the voltage-dependent opening. In contrast, gamma-HCH (30 microM) suppressed the activity of BK(Ca) channels. Under the current-clamp mode, delta-HCH (30 microM) reduced the firing rate of spontaneous action potentials; however, gamma-HCH (30 microM) increased it. In neuroblastoma IMR-32 cells, delta-HCH also increased the amplitude of I(K(Ca)) and stimulated the activity of intermediate-conductance K(Ca) channels. This study provides evidence that delta-HCH is an opener of K(Ca) channels. The effects of delta-HCH on these channels may partially, if not entirely, be responsible for the underlying cellular mechanisms by which delta-HCH affects neuronal or neuroendocrine function.

PMID: 10779368, UI: 20242000

Mitochrondria

A small organelle found inside of all cells that makes the energy molecules of the cell. Exercise promotes the formation of more mitochondria.

Mitochondria were supposed to be a major source of biological and toxicological radical formation thereby inducing and / or promoting a great variety of pathological disturbances in cells, organs and the whole organism. Aim of recent studies is to elucidate conditions for the transformation of cell respiration to a source of toxic oxygen radicals. Ischemia/reperfusion injury, different drugs , e.g. adriamycin, aging and several lipophilic compounds (atrazine, toluol, lindane, benzene, etc.) were found to trigger the production of reactive oxygen species in mitochondria and to impair energy supply to the cell.

Multiple chemical sensitivities and neurotoxic responses

Lohmann K Prohl A Schwarz E

Vielfache Chemikalienunvertraglichkeit (Multiple Chemical Sensitivity Disorder) bei Patienten mit neurotoxischen Gesundheitsstorungen.

In: Gesundheitswesen (1996 Jun) 58(6):322-31 (Published in German)

The data of 466 subjects suffering from neurologic disorders which are suggested to be caused by neurotoxic agents in their environment retrospectively was evaluated and documented. Among these cases there were 151 subjects with symptoms of Multiple Chemical Sensitivity Disorder (MCSD). The relationship between the neurological health impairments and neurotoxic agents in the environment of these patients was characterised using five different categories (probable = A, possible = B, uncertain = C, unclarified = D, not probable = E). From the 466 patients 320 subjects (69%) could be assigned to the categories A and B, respectively. Within theses 320 cases with chronic neurotoxic health impairments 136 subjects (79 females and 57 males) showed signs of MCSD. Age and gender of cases as well as duration and character of exposure to neurotoxic substances retrospectively were assessed from the explicit files of the patients, which had been made anonymous for this purpose. Frequency of characteristic symptoms of neurotoxicity were analysed. Results are given for patients with neurotoxic health impairments with MCSD (n = 136) and without MCSD (n = 184). Neurotoxic substances which were used as indoor wood preservatives (mainly Pentachlorophenol and/or Lindane) were found to be the causative agents in 63% of the cases with neurotoxic health impairments and MCSD. Other important neurotoxic substances to which the patients were mainly exposed were organic solvents (25%), formaldehyde (15%), dental materials (15%), pyrethroides (13%), and other biocides (19%) (multiple exposures were possible). The time of exposure was calculated as being > or = 10 years for 55% of the patients with MCSD and for 50% of the group with neurotoxic health impairments but without MCSD. Out of the 184 cases with neurotoxic health impairments but without MCSD there were 22%, and out of the 136 cases with MCSD there were 39% who showed all symptoms of chronic fatigue syndrome. 53% of the cases with MCSD had an allergic disposition compared to only 20% of the cases without MCSD. This work is not a controlled epidemiological study but a retrospective documentation and evaluation of data related to environmental medicine. With the present documentation in this purely descriptive manner the proof of a causal relationship was not possible or intended. But because corresponding epidemiological studies are lacking, this documentation can give important information on characteristic features of Multiple Chemical Sensitivity Disorder and chronic neurotoxic health impairments. Such information is essential for planning and carrying out epidemiological studies urgently needed in this field.

Known to bind to GABAA receptor.

We believe that lindane may also bind to the PBR.

 www.mcnair.ucdavis.edu/presentations/1998/

Tochman, Anna
Jaczewskiego 2
20-950 Lublin
Poland

Tochman A., Kaminski R., Tomczyk T.
Institute of Agricultural Medicine, Medical University School

Modification of the convulsive activity of lindane by antiepileptic drugs and calcium channel antagonists

Lindane, gamma-isomer of hexachlorocyclohexane is widely used as a pesticide in agriculture and against ectoparasites in dermatology. It is known from neurotoxic effects which involve induction of seizure activity. This activity seems to be mainly related to neuronal inhibition of gamma-aminobutyric acid (GABA) transmission. However, the influence of lindane upon intracellular calcium level and excitatory amino acid transmission is also postulated. In our study, we intended to determine whether antiepileptic drugs and calcium channel antagonists could modify the convulsive activity of lindane. Experiments were carried out on male mice. The following antiepileptic drugs (AEDs) were tested: carbamazepine (CBZ), diphenylhydantoin (DPH), clonazepam (CLO), phenobarbital sodium (PB), valproate magnesium (VPA), ethosuximide (ETX), diazepam (DZP), lamotrigine (LTG) and vigabatrin (VGB). Moreover, the following calcium channel antagonists were used: flunarizine (FLU), nimodipine (NIM), nifedipine (NIF), nicardipine (NIC) and amlodipine (AML). All substances were administered intraperitoneally. The convulsive dose (CD97) of lindane for the induction of clonic and tonic seizures was estimated. Subsequently, the effective doses (ED50) of drugs against lindane-induced seizures were assessed. DZP, CLO, PB, VPA and ETX were effective against clonic and tonic seizures. CBZ, DPH and LTG were only able to protect animals from tonic seizures. VGB was ineffective against either clonic or tonic convulsions. None of the studied calcium channel antagonists were effective against clonic and tonic seizures, only AML significantly prolonged the latency to seizures induced by lindane. In spite of multiple mechanisms of convulsive action of lindane, the most effective against lindane-induced seizures appeared AEDs that mainly act on GABAA receptor complex (DZP, CLO, PB). However, ETX and VPA able to antagonise calcium influx through low voltage-activated calcium channel were also effective. Surprisingly, antagonists of high-voltage activated calcium channel were completely ineffective.

http://www.ukrv.de/esc/ESC/1998/ABS/PH/PH17.HTM