Mecamylamine effects on haloperidol-induced catalepsy and defecation.

Recent clinical experience with Tourette syndrome (TS) patients suggests that the nicotinic receptor antagonist, mecamylamine (Inversine), may be a useful adjunct to neuroleptic therapy for controlling tic symptom. This is consistent with previous preclinical findings demonstrating that mecamylamine can potentiate the cataleptic effects of neuroleptics in rats. However, these earlier preclinical studies employed high doses (1-2.5 mg/kg) of mecamylamine that may not be clinically relevant since human doses of mecamylamine used to treat TS have been much lower (0.03-0.1 mg/kg). In order to test the potential therapeutic properties of mecamylamine preclinically, we conducted catalepsy experiments in rats employing both a low and high dose of mecamylamine in combination with haloperidol. Sixty-four male Sprague Dawley rats were randomized into four treatment groups (n = 16/group). Each rat received an injection of either saline or mecamylamine (0.1 or 3.0 mg/kg s.c.) followed one hour later with a second injection of either saline or haloperidol (0.4 mg/kg s.c.). The bar test was used to measure duration of catalepsy at 3 hrs following the second injection. The results demonstrated that only the mecamylamine treated rats showed statistically significant haloperidol-induced catalepsy when measured at 3 hrs. In addition, haloperidol-induced defecation was not affected by the 0.1 mg/kg mecamylamine dose, but completely abolished by the 3.0 mg/kg dose. These findings suggest that a clinically relevant dose of mecamylamine (0.1 mg/kg) can affect the duration of haloperidol-induced catalepsy without having significant effects on gastrointestinal function.

A kringle-specific monoclonal antibody.

Kringle domains are found in several plasma proteins of blood coagulation and fibrinolysis. A murine monoclonal antibody, designated alpha HII-5, was produced against a synthetic peptide representing residues 216-231 of human prothrombin kringle 2. The sequence of the hexadecapeptide (Glu-Asn-Phe-Cys-Arg-Asn-Pro-Asp-Gly-Asp-Glu-Glu-Gly-Val-Gly-Cys) is conserved in several kringle-containing proteins, represents a predicted region of high local hydrophilicity in prothrombin kringle 2, and contains the anionic (Asp-223 and Asp-225) residues that contribute to lysine binding by plasminogen kringle 4. In a solution-phase immunoassay, antibody alpha HII-5 bound prothrombin and the kringle 5 light chain fragment of plasminogen (miniplasminogen), but not plasminogen or plasmin. In contrast, using a solid-phase assay with antigen immobilized onto a surface (polystyrene microtiter plates, glass, or nitrocellulose) antibody alpha HII-5 specifically bound prothrombin, plasminogen, recombinant tissue plasminogen activator (tPA), and the apo(a) subunit of lipoprotein(a). By immunoblotting analysis antibody alpha HII-5 bound determinants on prothrombin fragment 2 and plasminogen kringle 5. These observations suggest that a subset of kringle domains on plasma proteins, including prothrombin kringle 2 and plasminogen kringle 5, contains a homologous antigenic determinant in the region of the kringle lysine-binding site. In contrast to prothrombin kringle 2, the homologous peptide site on plasminogen is not available for antibody binding except when plasminogen is adsorbed to a nonphysiological surface, or when kringles 1-4 are removed.