Central Nervous System Depressant Properties Research Articles

Preliminary Study on the In vivo Anti-neuroinflammatory Effects of Khaya grandifoliola and Cymbopogon citratus Polysaccharide Fractions

Aims: To determine the effects of polysaccharide fractions named KGF and CCF respectively for Khaya grandifoliola stem bark and Cymbopogon citratus leaves on Central Nervous System (CNS) depression and on systemic lipopolysaccharide (LPS)-induced brain inflammation and hyperalgesia in BALB/c.
 Methodology: BALB/c mice weighing about 25-35 g were used for the experimentation. Depressant effects of polysaccharide fractions were firstly evaluated using Rota Rod and Actophotometer apparatus. Secondly, LPS or saline solution (5 mg/kg) was Intraperitoneally administered (i.p.) 1 hour after oral administration of polysaccharide fractions (100 mg/kg test dose, p.o.) or distilledwater. Then, the hot plate and tail-flick models were performed 1 hour after LPS injection to determine thermal hyperalgesia and brain inflammation, was examined 3 hours after LPS injection by Luminex assay.
 Results:Systemic LPS administration resulted in a reduction of pain response latency and an increasing expression of nuclear factor-κB (NF-κB) and pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, tumor necrosis factor- α (TNF-α) genes in brain after 24 hours. From the results it was observed that treatment with KGF and CCF (100 mg/kg, p.o) significantly attenuated LPS-induced hyperalgesia and overexpression of brain levels of IL-1β, IL-6 and TNF-α genes dependent on inhibition of the NF-κB signaling pathway in BALB/c without CNS depressant properties.
 Conclusion: The present findings confirm the potential of KGF and CCF in the treatment of neuroinflammation-related diseases and it warrant further testing for the development of a new chemical entities. However further studies are required for determination of effective dose and mechanism of action associated.

DESIGN AND SYNTHESIS OF 4-SUBSTITUTED QUINAZOLINE DERIVATIVES FOR THEIR ANTICONVULSANT AND CNS DEPRESSANT ACTIVITIES

<p><strong>Objective: </strong>The present work is designed to synthesise some isomeric new series of Quinazoline-4-one/4-thione derivatives, based on the pharmacophoric model of central nervous system (CNS) activity by structural modifications retaining the essential structural features for the activity and evaluated for their anticonvulsant and CNS depressant properties.</p><p><strong>Methods: </strong>A series of 7-chloro-3-[substituted (amino/phenylamino)]-2-phenyl quinazolin-4 (3H)-one/thione derivatives and 1-(7-chloro-4-oxo/-2-phenylquinazoline-3 (4H-yl)) substituted urea derivatives were prepared. The reaction scheme proceeds through the intermediate 7-chloro-2-phenyl-4H-benzo[d] [1, 3] oxazin-4-one. The structures of the newly synthesised compounds were characterized from infrared (IR), <sup>1</sup>H nuclear magnetic resonance (NMR) and mass spectra (m/z) and elemental analysis. The anti-convulsant and CNS depressant activity were investigated by maximum electroshock (MES) seizure test and porsolt’s behavioural despair test (forced swimming) respectively. The rota-rod test was performed to assess any probable changes in motor coordination induced by the test compounds.</p><p><strong>Results: </strong>The physicochemical and spectroscopic data clearly confirmed the synthesis of quinazoline derivatives with a common skeleton. The synthesised compounds were evaluated for their anticonvulsant and CNS depressant properties. Among them, six compounds <strong>(IIc, </strong>IIg, IIj, IIIc, IIIg, IIIj) exhibited a good activity profile in CNS depressant activity. Five compounds (IIc, IIg, IIj, IIIg, IIIh) showed protection against MES-induced seizures.</p><p><strong>Conclusion: </strong>The Quinazoline derivatives obtained from this research work indicates that the methyl/methoxy group in phenyl ring, amine and thiourea substitution at 3<sup>rd</sup> position of quinazoline derivatives are essential for CNS depressant activity as well as anticonvulsant activity. Compounds IIc, IIg, IIj, IIIc, IIIg, IIIj, and IIIh were found to be a potent compound which may be effective as a potential source for the development of CNS depressant and anti-convulsant drugs with lesser side effects</p>

English

Salvia lavandulifolia Vahl. is a plant of Iberian Peninsula origin that belongs to the genus Salvia. Phytochemical evaluation of the plant indicated the presence of flavonoids, triterpenoids, diterpenoids and monoterpenes. Its essential oil is rich in various bioactive compounds (like 1,8-cineole or α-pinene). The plant has been traditionally used for its spasmolytic, antiseptic, analgesic, sedative and anesthesic activities. Pharmacological studies of the plant have demonstrated its reputation as aromatic plant to enhance memory and anti-dementia drug by the inhibition of cholinesterase enzyme. The species also possesses a wide range of pharmacological uses including: antioxidant, anti-inflammatory, estrogenic and central nervous system depressant properties, relevant to the treatment of Alzheimer´s disease. The present review summarizes the information concerning the botany, ethnopharmacology, phytochemistry, pharmacological activities and toxicity of the Salvia lavandulifolia plant, because these findings suggest the need for further research of this plant.

Determination of mass spectral and fragmentation pattern of some centrally-acting 1,3-cyclohexandione derivatives

Many of the drugs currently used in clinical practice possess undesirable side effects, which make some patients less inclined to comply with recommended dosage regimen. Also, therapeutic failure has resulted from development of resistance by organisms to some drugs including antimalarials and antibiotics. There is need therefore, to find safer and effective alternatives devoid of the problems stated earlier. The cyclohexanediones are quite reactive and various workers have obtained several derivatives, which have been found to be biologically active with some possessing useful antimicrobial and herbicidal activities. The 1, 3-cyclohexanedion carboxylate and nine aryl- and arylalkylamino derivatives: ethyl 4-hydroxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate: ethyl 6-methyl-2-oxo-4-phenylamino-3-cyclohexene-1-carboxylate; ethyl 4-benzylamino 6-methyl-2-oxo-3-cyclohexene-1-carboxylate; ethyl 6-methyl-2-oxo-4-(2'-phenylethylamino)-3-cyclohexene-1-carboxylate; 6-methyl-2-oxo-4-phenylamino-3-cyclohexene-1-(N-phenyl)-carboxamide; 6-methyl-2-oxo-4-phenylamino-3-cyclohexene-1-(N-benzyl)-carboxamide; 4-benzylamino-6-methyl-2-oxo-3-cyclohexene-1-(N-benzyl) carboxamide; 4-benzylamino-6-methyl-2-oxo-3-cyclohexene-1-(N-2'-phenylethyl)-carboxamide; and 6-methyl-2-oxo-4-(2'-phenylethylamino)-3-cyclohexene-1-(N-benzyl)-carboxamide were synthesized. Phenyl, benzyl, phenylethyl, and their amino and carboxy derivatives fragment ions observed in the mass spectra of the corresponding compounds. Most of the compounds except those with phenylamino substituent at the 4-C caused reduction in activity of and sedation in chicks, indicating that they possessed central nervous system depressant properties. Thus they could be useful in the treatment of mental agitations and as muscle relaxants Key words: Cyclohexanediones; Mass spectra; Fragmentation pattern; C.N.S. depressant. Nig. J. Pharm. Res. 3(1) 2004: 72-81

Galphimine B modulates synaptic transmission on dopaminergic ventral tegmental area neurons.

Galphimine B (GB) is a bioactive compound isolated from the plant Galphimia glauca Cav. (Malpighiaceae) and has been shown to have central nervous system depressant properties. In an earlier study, it was reported that both systemic and local administration of GB modified the extracellular spontaneous spiking activity in the ventral tegmental area (VTA) neurons. In the present study we analyzed the synaptic effects of this compound on dopaminergic neurons. Recordings were made in brain slices using intracellular and patch-clamp techniques, in dopaminergic (DA) VTA neurons. Spontaneous miniature excitatory postsynaptic currents (mEPSCs), excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic potentials (IPSPs) were recorded in control situation and after bath infusions of several concentrations of GB (1 microM-5 mM), GABA (1 nM-100 microM) and the GABA A blockers, picrotoxin (100 microM) and bicuculline (10 microM), and GABA B blocker saclofen (200 microM). GB administration reduced the frequency (p < 0.05) but not the amplitude of mESPCs. However, GABA (IC 50 = 645 nM) and GB (IC 50 = 174.5 microM) infusion significantly reduced the amplitude of stimuli induced EPSCs, Bicuculline (10 microM) co-administration only reduced GABA effects and did not modify the GB depressant action. Finally, isolated GABAergic IPSPs were modified by the addition of picrotoxin, but GB had no effect on these evoked synaptic responses. The present results indicate that GB modifies synaptic activity on dopaminergic VTA neurons by a non-GABAergic mechanism.

Some effects of Salvia aegyptiaca L. on the central nervous system in mice

Salvia aegyptiaca L. is used for treating various unrelated conditions that include nervous disorders, dizziness, trembling, diarrhoea and piles. This work examines some effects of the crude acetone and methanol extracts of the plant given at single oral doses of 0.25, 0.5, 1 or 2 g/kg, on the central nervous system (CNS) in mice. The extracts were also tested for anti-inflammatory and antipyretic actions. Several models of nociception have been used to examine the analgesic effect of the extract. In treated mice, the extracts caused dose-related inhibition of acetic acid-induced abdominal constriction, and significantly reduced formalin-induced pain. Treatment with the extracts at doses of 0.5 and 1 g/kg significantly increased the reaction time in the hot-plate test. In treated mice both extracts caused significant and dose-related impairment of the sensorimotor control and motor activity. Treatment with both extracts did not significantly affect the rectal temperature of normothermic mice. The methanol extract (0.5 and 1.0 g/kg) did not affect the rectal temperature of hyperthermic mice, but the acetone extract was effective in significantly reducing the rectal temperature of hyperthermic mice, 0.5 and 1 h after administration of the extract at doses of 0.25–2 g/kg. It is concluded that the crude methanol and acetone extracts of S. aegyptiaca have CNS depressant properties, manifested as antinociception and sedation. Both extracts have some anti-inflammatory and antipyretic actions. On the whole, the acetone extract appeared to be slightly more effective than the methanol extract in this regard.

Ethyl 1-(2-cyanoethyl)-3,5-dimethyl-1H-indole-2-carboxylate

The title compound, C16H18N2O2, is an important precursor in the synthesis of 1,2,3,4-tetrahydropyrazinoindoles, which show excellent antihistamine, antihypertensive and central nervous system depressant properties. The carbethoxy group attached to C2 and the planar cyanoethyl group attached to N1 make dihedral angles of 11.0(4) and 75.0(3)degrees, respectively, with the mean plane of the indole ring, The C-C=N chain is linear with a bond angle of 179.3 (4)degrees.

Galphimine-B modifies electrical activity of ventral tegmental area neurons in rats.

Galphimine-B (G-B) is a bioactive compound isolated from the plant Galphimia glauca Cav. (Malpighiaceae) with central nervous system depressant properties previously described. In the present study, extracellular spiking activity records in either somatosensorial cortex or ventral tegmental area (VTA) neurons, were performed in rats after i.p. or local administration of G-B. None of the cortical neurons displayed significant changes induced by any of the applied doses. In VTA cells, two patterns of electrical discharge were recorded, bursting (57%) and nonbursting (43%) types. Systemic administration of G-B induced excitatory effects in neurons with a bursting firing pattern and mixed responses on nonbursting units. When this compound was applied locally by microiontophoresis, most of the bursting and nonbursting spiking neurons showed a firing depression and only a few of the nonbursting neurons showed an increment of discharge frequency. These results are important since VTA is a major dopaminergic center responsible for the innervation of the prefrontal cortex, nucleus accumbens and entorhinal region. These areas are targets for the action of antipsychotic drugs.

Sites of action of gamma-hydroxybutyrate (GHB)--a neuroactive drug with abuse potential.

This review highlights the biochemistry, pharmacology, and toxicology of the naturally-occurring fatty acid derivative, gamma-hydroxybutyrate (GHB). GHB is derived from gamma-aminobutyric acid (GABA) and is proposed to function as an inhibitory chemical transmitter in the central nervous system. When administered in pharmacological doses, its powerful central nervous system depressant effects are readily observed. Although some of the neurophysiological actions of GHB could involve alterations in dopaminergic transmission in the basal ganglia, both its physiological and pharmacological actions are probably mediated through specific brain receptors for GHB. In addition, GHB might mediate some of its effects through interaction with the GABA(B) receptor. Experimentally, GHB has been used as a model for petit mal epilepsy; clinically, it has been used as a general anesthetic and as a drug to treat certain sleep disorders and related conditions. Owing to the purported ability of GHB to induce a state of euphoria, recreational use of this substance is popular. Although no deaths or long-term problems have been associated with GHB abuse, symptoms of GHB intoxication can be severe. The continued potential for GHB abuse makes it imperative for clinical toxicologists to be aware of the effects of this agent. Future research on the mechanism of action of GHB is needed to elucidate both its central nervous system depressant properties and its ability to effect a state of well-being.

CENTRAL NERVOUS SYSTEM ACTIVITY OF RHAZYA STRICTA (DECNE) IN MICE

1. The effects of orally administered aqueous lyophilized extract of the leaves of Rhazya stricta (2, 4 & 8 g/kg) on aspects of nervous system function were investigated in mice. 2. In three antinociceptive tests (hot plate, abdominal constriction, and warm water tail flick tests), the extract exhibited dose-dependent and significant antinociceptive activity. Naloxone was ineffective in antagonizing the analgesic effect of Rhazya stricta on tail-flick and abdominal constriction tests, possibly indicating that this effect occurs via non-opiate pathways. 3.Pretreatment of mice with the xenobiotic metabolizing enzymes inhibitor cimetidine (50 mg/kg) did not significantly alter the antinociceptive action of the extract, indicating that the effect is probably due to the parent compound(s) present in the extract and not to metabolites thereof. 4. Rhazya stricta produce dose-dependent sedation, decreased motor activity, and impaired motor control. Time spent on a rotarod treadmill was significantly decreased after treatment with the extract. 5. Rhazya stricta extract (8 g/kg) produced a degree of sedation comparable to that produced by diazepam (5-10 mg/kg), and also significantly increased the reaction time of the tail-flick test, an action which was not produced by diazepam. 6. Administration of R. stricta extract potentiated pentobarbitone sleeping time in a dose dependent manner. The extract did not significantly antagonize picrotoxin induced convulsions. The extract (4 and 8 g/kg) significantly decreased the rectal temperature of normothermic and hyperthermic mice. 7. Pretreatment with R. stricta extract (8 g/kg) completely prevented the occurrence of aggressive behaviour in male mice. 8. It is concluded that the crude extract of R. stricta has central nervous system depressant properties.

Effect of taurine on ethanol-induced sleep time in mice genetically bred for differences in ethanol sensitivity

Long Sleep (LS) and Short Sleep (SS) mice were used in this study to investigate the interaction between ethanol and taurine. Sleep time (hypnosis) was selected as an index of ethanol-induced central nervous system depression. In order to achieve a similar degree of central nervous system depression with ethanol, SS and LS mice received 5.3 and 3.0 g/kg, IP, of ethanol, respectively. When taurine (7.5, 15 and 25 μmol/kg) was administered intracerebroventricularly (ICV) to LS and SS mice immediately after regaining the righting reflex following ethanol injection, a return to sleep time was produced. This effect of taurine was immediate in onset and occured in a dose-dependent fashion. LS mice exhibited a greater effect from taurine administration than SS mice. In another experiment LS and SS mice were given ICV TAG, a taurine antagonist (6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1, 1-dioxide HCl), which significantly reduced the effect of taurine to produce a return to sleep time in the presence of ethanol. TAG did not affect ethanol-induced sleep time. In control experiments, in the absence of ethanol, neither taurine (25 μmol/kg, ICV) nor TAG (1 μmol/kICV) caused a significant loss of the righting reflex (sleep time). When pentobarbital (50 mg/kg, IP) was injected instead of ethanol in the sleep time experiments, taurine (7.5, 15 and 25 μmol/kg, ICV) produced a return to sleep time in LS and SS mice that resembled the effect of taurine with ethanol in SS mice. These results indicate that taurine (ICV) can enhance the central depressant action of ethanol and pentobarbital and that the greatest effect of taurine occurred with LS mice in the presence of ethanol. It is possible that taurine may have some role in the central nervous system depressant properties of ethanol.

Gamma-Aminobutyric acid esters. 2. Synthesis, brain uptake, and pharmacological properties of lipid esters of gamma-aminobutyric acid.

Two lipid esters of U-14C-labeled and unlabeled gamma-aminobutyric acid (GABA) were synthesized to test the possibility that natural lipid analogues, which resemble normal components of lipid bilayer membranes, can penetrate the blood-brain barrier and transport exogenous GABA to the brain. The uptake of 1-linolenoyl-2,3-bis(4-aminobutyryl)propane-1,2,3-triol and 1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol into mouse brain relative to liver was found to be, respectively, 75- and 127-fold greater than that of free GABA. The results indicate that there is little or no blood-brain barrier for the GABA ester molecules at doses up to 0.36 mmol/kg. Both ester compounds, but neither free GABA nor the lipid components delivered systemically, demonstrated central nervous system depressant properties by inhibiting the general motor activity of mice. Brain tissue has esterase activity which can release GABA from these compounds. This suggests that these compounds function as "prodrugs" to release GABA in the CNS.

Mechanism of the γ-hydroxybutyrate-induced increase in brain dopamine and its relationship to “sleep”

The naturally occurring central nervous system depressant γ-hydroxy-butyrate (GHB) and its lactone precursor, γ-butyrolactone (GBL) cause a marked and selective increase in brain dopamine. Concomitant with the increase in brain dopamine, homovanillic acid, a metabolite of brain dopamine, is decreased. GBL also causes a selective increase in the specific activity of brain dopamine but not of brain norepinephrine when rats are injected with 14C-tyrosine. This is probably the result of a compensatory activation of dopaminergic neurons because of a blockade in dopamine release induced by GHB. When catecholamine biosynthesis is inhibited by administration of α-methyl- p-tyrosine, GBL completely blocks the disappearance of subcortical dopamine but exerts no antagonism on the disappearance of subcortical norepinephrine. These observations are suggestive that GBL increases brain dopamine primarily by selectively blocking the release of this monoamine from dopamine containing neurons. Indirect evidence is also presented which suggests that the central nervous system depressant properties of GHB may be related to this block in the release of brain dopamine.

CENTRAL DEPRESSANT EFFECTS OF SOME IMIDAZOLIDINONE DERIVATIVES

In the course of our investigation on a series of synthetic imidazolidinone derivatives we have found that some of these substances had central nervous system depressant properties in experimental animals. Among these were 4, 5-bis-alkyloxy or -alkenyloxy derivatives of 2-imidazolidinone with the following chemical structures: These compounds, for the sake of convenience, will be referred to by their code numbers SRC-906 and SRC-916 respectively. SRC-916 is a new substance which has never been disclosed in any printed articles. SRC-906 and -916 are colorless, white needle, stable crystalline which are insoluble in water, soluble in methanol, chloroform and benzene. The melting point of SRC-906 is 104°C-105°C and of SRC-916 is 68°C-70°C. The purpose of this paper is to evaluate the effect of SRC-906 and SRC-916 as compared with that of Ethinamate on the following activities: 1) acute toxicity and hypnotic activity in mice, 2) anticonvulsant activity in mice, 3) potentiation of barbiturate hypnosis in mice, 4) sedative and hypnotic activity in cats and 5) effect on electroencephalogram of cats.